5-Lipoxygenase-Activating Protein (FLAP) Inhibitors

ABSTRACT

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.

RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.60/734,030, entitled “5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP)INHIBITORS” filed on Nov. 4, 2005; U.S. Provisional Application No.60/747,174, entitled “5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP)INHIBITORS”, filed on May 12, 2006; and U.S. Provisional Application No.60/823,344, entitled “5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP)INHIBITORS”, filed on Aug. 23, 2006, all of which are hereinincorporated by reference.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments comprising such compounds,and methods of using such compounds to treat or prevent diseases orconditions associated with 5-lipoxygenase-activating protein (FLAP)activity.

BACKGROUND OF THE INVENTION

The protein 5-lipoxygenase-activating protein (FLAP) is associated withthe pathway of leukotriene synthesis. In particular,5-lipoxygenase-activating protein (FLAP) is responsible for bindingarachidonic acid and transferring it to 5-lipoxygenase. See, e.g.,Abramovitz, M. et al., Eur. J. Biochem. 215:105-111 (1993).5-lipoxygenase can then catalyze the two-step oxygenation anddehydration of arachidonic acid, converting it into the intermediatecompound 5-HPETE (5-hydroperoxyeicosatetraenoic acid), and in thepresence of FLAP convert the 5-HPETE to Leukotriene A₄ (LTA₄).

Leukotrienes are biological compounds formed from arachidonic acid inthe leukotriene synthesis pathway (Samuelsson et al, Science, 220,568-575, 1983; Cooper, The Cell, A Molecular Approach, 2nd Ed. SinauerAssociates, Inc., Sunderland (A), 2000). They are synthesized primarilyby eosinophils, neutrophils, mast cells, basophils, dendritic cells,macrophages and monocytes. Leukotrienes have been implicated inbiological actions including, by way of example only, smooth musclecontraction, leukocyte activation, cytokine secretion, mucous secretion,and vascular function.

SUMMARY OF THE INVENTION

Presented herein are methods, compounds, pharmaceutical compositions,and medicaments for (a) diagnosing, preventing, or treating allergic andnon-allergic inflammation, (b) controlling signs and symptoms that areassociated with inflammation, and/or (c) controlling proliferative ormetabolic disorders. These disorders may arise from genetic, iatrogeic,immunological, infectious, metabolic, oncologic, toxic, and/or traumaticetiology. In one aspect, the methods, compounds, pharmaceuticalcompositions, and medicaments described herein comprise5-lipoxygenase-activating protein (FLAP) inhibitors described herein.

In one aspect provided herein are compounds of Formula (E),pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides,pharmaceutically active metabolites, pharmaceutically acceptableprodrugs, and pharmaceutically acceptable solvates thereof, whichantagonize or inhibit FLAP and may be used to treat patients sufferingfrom leukotriene-dependent conditions or diseases, including, but notlimited to, asthma, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, rhinitis, arthritis, allergy,psoriasis, inflammatory bowel disease, adult respiratory distresssyndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxicshock, proliferative disorders and inflammatory conditions.

Formula (E) is as follows:

wherein,

-   -   Z is OC(R₁)₂[C(R₂)₂]_(n), [C(R₂)₂]_(n), or [C(R₂)₂]_(n)C(R₁)₂O        wherein each R₁ is independently H, CF₃, or an optionally        substituted lower alkyl and two R₁ on the same carbon may join        to form a carbonyl (═O); and each R₂ is independently H, OH,        OMe, CF₃, or an optionally substituted lower alkyl and two R₂ on        the same carbon may join to form a carbonyl (═O); each n is        independently 0, 1, 2, or 3;    -   Y is -L₁-(substituted or unsubstituted heteroalicyclic group),        provided that when the heteroatom is directly bound to Z, the        heteroalicyclic group is substituted;        -   where L₁ is a bond, a substituted or unsubstituted alkyl,            substituted or unsubstituted alkenyl, or substituted or            unsubstituted alkynyl, a substituted or unsubstituted            heterocycle, a substituted or unsubstituted cycloalkyl, a            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted heteroalkenyl, or a substituted or            unsubstituted heteroalkynyl;        -   where each substituent is (L_(s)R_(s))_(j), wherein each            L_(s) is independently selected from a bond, —O—, —C(═O)—,            —S—, —S(═O)—, —S(═O)₂—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—,            —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—,            —C(O)O—, —OC(O)—, C₁-C₆ alkyl, C₂-C₆ alkenyl, —C₁-C₆            fluoroalkyl, heteroaryl, aryl, or heteroalicyclic group; and            each R_(s) is independently selected from H, halogen,            —N(R₄)₂, —CN, —NO₂, N3, —S(═O)₂NH₂, lower alkyl, lower            cycloalkyl, —C₁-C₆ fluoroalkyl, heteroaryl, or heteroalkyl;            where j is 0, 1, 2, 3, or 4;        -   each R₄ is independently selected from H, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl; or two R₄ groups can            together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   R₆ is H, L₂-(substituted or unsubstituted alkyl),        L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or        unsubstituted alkenyl), L₂-(substituted or unsubstituted        cycloalkenyl), L₂-(substituted or unsubstituted heteroalicyclic        group), L₂-(substituted or unsubstituted heteroaryl), or        L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O,        S, —S(—O), —S(═O)₂, C(O), —CH(OH), -(substituted or        unsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted        C₂-C₆ alkenyl);    -   R₇ is L₃-X-L₄-G₁, wherein,        -   L₃ is a bond, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            heteroalicyclic group;        -   X is a bond, O, —C(═O), —CR₉(OR₉), S, —S(═O), —S(═O)₂, —NR₉,            —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NR₉—,            —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl,            aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—,            —OC(═NR₁₀)—, or —C(═NR₁₀)O—;        -   L₄ is a bond, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl;        -   G₁ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉,            —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂N—HC(O)R₉, CN, N(R₉)₂,            —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,            —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)NR₉)₂,            —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈,            —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted            alkyl), -L₅-(substituted or unsubstituted alkenyl),            -L₅-(substituted or unsubstituted heteroaryl), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is            —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);        -   or G₁ is W-G₅, where W is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroalicyclic group or            substituted or unsubstituted heteroaryl and G₅ is H,            tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃,            —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,            —C(═NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,            —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉,            —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈;        -   each R₈ is independently selected from substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl;        -   each R₉ is independently selected from H, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl; or two R₉ groups can            together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;            or R₈ and R₉ can together form a 5-, 6-, 7-, or 8-membered            heterocyclic ring and        -   each R₁₀ is independently selected from H, —S(═O)₂R₉,            —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;    -   R₅ is H, halogen, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted O—C₁-C₆ alkyl;    -   R₁₁ is L₇-L₁₀-G₆; wherein L₇ is a bond, —O, —S, —S(═O), —S(═O)₂,        —NH, —C(O), —C(O)NH, —NHC(O), (substituted or unsubstituted        C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);        -   L₁₀ is a bond, (substituted or unsubstituted alkyl),            (substituted or unsubstituted cycloalkyl), (substituted or            unsubstituted cycloalkenyl), (substituted or unsubstituted            heteroaryl), (substituted or unsubstituted aryl), or            (substituted or unsubstituted heteroalicyclic group), and        -   G₆ is H, CN, SCN, N₃, NO₂, halogen, OR₉, —C(═O)CF₃,            —C(═O)R₉, —SR₈, —S(═O)R₈, —S(═O)₂R₈, N(R₉)₂, tetrazolyl,            —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —C(O)NHS(—O)₂R₈,            —S(═O)₂NHC(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R₉)₂,            —NR₉C(═CR₁₀)N(R₉)₂, -L₅-(substituted or unsubstituted            alkyl), -L₅-(substituted or unsubstituted alkenyl),            -L₅-(substituted or unsubstituted heteroaryl), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is            —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);        -   or G₆ is W-G₇, wherein W is (substituted or unsubstituted            cycloalkyl), (substituted or unsubstituted cycloalkenyl),            (substituted or unsubstituted aryl), (substituted or            unsubstituted heteroalicyclic group) or a (substituted or            unsubstituted heteroaryl) and G₇ is H, tetrazolyl,            —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃,            —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,            —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(—CR₁₀)N(R₉)₂,            —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉,            —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═C))R₈, or —S(═O)₂R₈,            —L₅-(substituted or unsubstituted alkyl), -L₅-(substituted            or unsubstituted alkenyl), -L₅-(substituted or unsubstituted            heteroalkyl), -L₅-(substituted or unsubstituted heteroaryl),            -L₅-(substituted or unsubstituted heteroalicyclic group), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is —NH,            —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);    -   R₁₂ is H, (substituted or unsubstituted C₁-C₆ alkyl), or        (substituted or unsubstituted C₂-C₄ alkenyl); or an active        metabolite, or solvate, or pharmaceutically acceptable salt, or        a pharmaceutically acceptable prodrug thereof.

For any and all of the embodiments (such as, e.g. Formula (E), Formula(E-I), and Formula (E-II)), substituents can be selected from among froma subset of the listed alternatives. For example, in some embodiments, Yis -L₁-(substituted or unsubstituted heteroalicyclic group). In furtheror alternative embodiments, the heteroalicyclic group is selected fromthe group consisting of a quinolizine, a dioxine, a piperidine, amorpholine, a thiazine, a tetrahydropyridine, a piperazine, aoxazinanone, a dihydropyrrole, a dihydroimidazole, a tetrahydrofuran, adihydrooxazole, an oxirane, a pyrrolidine, a pyrazolidine, adihydrothiophenone, an imidazolidinone, a pyrrolidinone, adihydrofuranone, a dioxolanone, a thiazolidine, a piperidinone, atetrahydronaphyridine, a tetrahydroquinoline, a tetrahydrothiophene, anindoline, a tetrahydroquinoline, and a thiazepane. In further oralternative embodiments, the heteroalicyclic group is selected from thegroup consisting of:

In further or alternative embodiments, R₆ is L₂-(substituted orunsubstituted alkyl), or L₂-(substituted or unsubstituted cycloalkyl),or L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(O)₂, —C(O), —CH(OH), or substituted or unsubstituted alkyl.

In further or alternative embodiments, R₇ is L₃-X-L₄-G₁; wherein, L₃ isa substituted or unsubstituted alkyl; X is a bond, O, —C(═O), —CR₉(OR₉),S, —S(═O), —S(═O)₂, —NR₉, —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂,—OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl,aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or—C(—NR₁₀)O—; and L₄ is a bond or a substituted or unsubstituted alkyl.

In further or alternative embodiments, G₁ is tetrazolyl, —NHS(═O)₂R₈,S(═O)₂N(R₉)₂, —OR₉, —C(—O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN,N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,—NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂,—CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, or G₁ is W-G₅,where W is a substituted or unsubstituted heteroalicyclic group orsubstituted or unsubstituted heteroaryl and G₅ is tetrazolyl,—NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈,—S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂,—C(O)NC(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or—S(═O)₂R₈.

In further or alternative embodiments, X is a bond, —O—, —CR₉(OR₉), S,—S(O), —S(O)₂, —NR₈, —O—N═CH, —CH═N—O, —NHC(═O), or —C(═O)NH.

In further or alternative embodiments, R₁₂ is H and R₁₁ is L₇-L₁₀-G₆,wherein: L₇ is a bond, (substituted or unsubstituted C₁-C₆ alkyl); andL₁₀ is a (substituted or unsubstituted aryl), (substituted orunsubstituted heteroaryl), or (substituted or unsubstitutedheteroalicyclic group). In further or alternative embodiments, L₁₀ is a(substituted or unsubstituted aryl).

In further or alternative embodiments, G₆ is W-G₇, wherein W is(substituted or unsubstituted heteroalicyclic group) or (substituted orunsubstituted heteroaryl) and G₇ is H, tetrazolyl, —NHS(═O)₂R₈,S(═O)₂N(R₉), OH, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,—C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CON(R₉)₂,-L₅-(substituted or unsubstituted alkyl), -L₅-(substituted orunsubstituted heteroaryl), -L₅-(substituted or unsubstitutedheteroalicyclic group), or -L₅-(substituted or unsubstituted aryl), L₅is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH, —C(O)O,or —OC(O).

In some embodiments, Z is [C(R₂)₂]_(n)C(R₁)₂O.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

In further or alternative embodiments, compounds provided herein, areinhibitors of 5-lipoxygenase-activating protein (FLAP). In further oralternative embodiments, compounds provided herein, are inhibitors of5-lipoxygenase-activating protein (FLAP), wherein the inhibitor isselective for FLAP. In further or alternative embodiments, the inhibitorhas an IC₅₀ of below 50 microM in FLAP binding.

In one aspect, provided herein is a compound selected from among:

-   (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 1-1);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-2);    (R)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 1-3);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-5-oxo-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-4);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-5-oxo-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid. (Compound 1-5);    3-[5-((R)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-6);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-7);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-8);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-9);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(2,2,2-trifluoro-acetyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-10);    2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-4,5-dihydro-imidazole-1-carboxylic    acid tert-butyl ester (Compound 1-11);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-12);    (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester (Compound 1-13);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2-morpholin-4-yl-2-oxo-ethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-14);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[(S)-1-(2,3-dihydro-1H-indol-2-yl)methoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-15);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-16);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(2-methyl-propane-2-sulfonyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-17);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-cyclopropanecarbonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-18);    3-[5-((S)-1-benzoyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-19);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-isobutyryl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-20);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-propionyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-21);    2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester (Compound 1-22);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2,3-dihydro-1H-indol-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-23);    3-[5-(1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-24);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(2-methyl-propane-2-sulfinyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-25);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-benzyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-26);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-27);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-28);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-(4-chloro-benzyl)-3-(3,3-dimethyl-butyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-29);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyryl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-30);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-ethyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-31);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-propyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-32);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-isobutyryl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-33);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclopropanecarbonyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-34);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-benzoyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-35);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclobutanecarbonyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-36);    3-[3-acetyl-5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-37);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-propionyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-38);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-isobutyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-39);    3-[5-((S)-t-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 140);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclobutylmethyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 141);    3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-ylmethoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-42);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(1-phenylacetyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 143);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenyl-propionyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 144);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenoxy-benzoyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-45);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(4-phenoxy-benzoyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-46);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-47);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-48);    3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-ylmethoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 149);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(1-phenylacetyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-50);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenyl-propionyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-51);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-((S)-2-phenyl-cyclopropanecarbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-52);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-{1-(pyridine-3-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-53);    3-[(3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-54);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-((R)-2-phenyl-cyclopropanecarbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-55);    3-[3-tert-butylsulfanyl-5-[(S)-1-(4-chloro-benzoyl)-pyrrolidin-2-ylmethoxy]-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-56);    3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-ylmethoxy}-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-57);    3-[5-{-[2-(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-ylmethoxy}-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-58);    2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-piperidine-1-carboxylic    acid tert-butyl ester (Compound 1-59);    2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-ethoxycarbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-piperidine-1-carboxylic    acid tert-butyl ester (Compound 1-60);    2-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-2-(2-ethoxycarbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic    acid 2-bromo-ethyl ester (Compound 1-61);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-62);    3-{1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-63);    (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-thiazol-2-yl-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 2-1);    3-[3-tert-butylsulfanyl-5-((S)-1-pyrrolidin-2-ylmethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 2-2);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 2-3);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 24);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-5);    3-{5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-6);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-7);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(2-methoxy-thiazol-4-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-8);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-9);    3-{3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-10);    3-(3-tert-butylsulfanyl-5-[(S)-1-(2-methoxy-acetyl)-2,3-dihydro-1H-indol-2-ylmethoxy]-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-11);    2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-1-morpholin-4-yl-ethanone    (Compound 3-1);    (R)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 3-2);    R)-2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 3-3);    1-{(R)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidin-1-yl}-ethanone    (Compound 3-4);    1-{(R)-2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl]-pyrrolidin-1-yl}-ethanone    (Compound 3-5); and    (S)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(3-hydroxy-2,2-dimethyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 3-6).

In one aspect, provided herein is a pharmaceutical compositioncomprising an effective amount of a compound provided herein, and apharmaceutically acceptable excipient.

In another aspect, provided herein is a method for treating inflammationin a mammal comprising administering a therapeutically effective amountof a compound provided herein to the mammal in need.

In yet another aspect, provided herein is a method for treating asthmain a mammal comprising administering a therapeutically effective amountof a compound provided herein to the mammal in need. In a further oralternative embodiment, provided herein is a method for treating asthmain a mammal comprising administering a therapeutically effective amountof a compound provided herein, wherein Z is [C(R₂)₂]_(n)C(R₁)₂O, to themammal in need.

In another aspect, provided herein is a method for treating respiratorydisease in a mammal comprising administering a therapeutically effectiveamount of a compound provided herein to the mammal in need. In a furtheror alternative embodiment, provided herein is a method for treatingrespiratory disease in a mammal comprising administering atherapeutically effective amount of a compound provided herein, whereinZ is [C(R₂)₂]_(n)C(R₁)₂O, to the mammal in need.

In another aspect, provided herein is a method for treatingcardiovascular disease in a mammal comprising administering atherapeutically effective amount of a compound provided herein to themammal in need.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

In another aspect are compounds presented in any of FIG. 8, 9, 10, or11, or pharmaceutically acceptable salts, pharmaceutically acceptableN-oxides, pharmaceutically active metabolites, pharmaceuticallyacceptable prodrugs, and pharmaceutically acceptable solvates thereof,which antagonize or inhibit FLAP and may be used to treat patientssuffering from leukotriene-dependent conditions or diseases, including,but not limited to, asthma, chronic obstructive pulmonary disease,pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis,allergy, psoriasis, inflammatory bowel disease, adult respiratorydistress syndrome, myocardial infarction, aneurysm, stroke, cancer,endotoxic shock, proliferative disorders and inflammatory conditions.

In another aspect are compounds presented in any of Tables 1, 2, or 3,or pharmaceutically acceptable salts, pharmaceutically acceptableN-oxides, pharmaceutically active metabolites, pharmaceuticallyacceptable prodrugs, and pharmaceutically acceptable solvates thereof,which antagonize or inhibit FLAP and may be used to treat patientssuffering from leukotriene-dependent conditions or diseases, including,but not limited to, asthma, chronic obstructive pulmonary disease,pulmonary hypertension, interstitial lung fibrosis, rhinitis, arthritis,allergy, psoriasis, inflammatory bowel disease, adult respiratorydistress syndrome, myocardial infarction, aneurysm, stroke, cancer,endotoxic shock, proliferative disorders and inflammatory conditions.

In further or alternative embodiments, the compounds described hereinmay be inhibitors of 5-lipoxygenase-activating protein (FLAP), while instill further or alternative embodiments, such inhibitors are selectivefor FLAP. In even further or alternative embodiments, such inhibitorshave an IC₅₀ below 50 microM in the FLAP binding assay.

In further or alternative embodiments, the compounds described hereinmay be included into pharmaceutical compositions or medicaments used fortreating a leukotriene-dependent or leukotriene mediated condition ordisease in a patient.

In another aspect the inflammatory conditions include, but are notlimited to, asthma, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, rhinitis, aortic aneurysm,myocardial infarction, and stroke. In other aspects the proliferativedisorders include, but are not limited to, cancer and noncancerousdisorders, including, but not limited to, those involving the skin orlymphatic tissues. In other aspects the metabolic disorders include, butare not limited to, bone remodeling, loss or gain. In additionalaspects, such conditions are iatrogenic and increases in, or abnormallocalization of, leukotrienes may be induced by other therapies ormedical or surgical procedures.

In other aspects, the methods, compounds, pharmaceutical compositions,and medicaments described herein may be used to prevent the cellularactivation of S-lipoxygenase, while in other aspects the methods,compounds, pharmaceutical compositions, and medicaments described hereinmay be used to limit the formation of leukotrienes. In other aspects,such methods, compounds, pharmaceutical compositions, and medicamentsmay comprise FLAP inhibitors disclosed herein for the treatment ofasthma by (a) lowering the concentrations of leukotrienes in certaintissue(s) of the body or in the entire body of a patient, (b) modulatingthe activity of enzymes or proteins in a patient wherein such enzymes orproteins are involved in the leukotriene pathway such as, by way ofexample, S-lipoxygenase-activating protein or 5-lipoxygenase, or (c)combining the effects of (a) and (b). In yet other aspects, the methods,compounds, pharmaceutical compositions, and medicaments described hereinmay be used in combination with other medical treatments or surgicalmodalities. In one aspect are methods for reducing/inhibiting theleukotriene synthetic activity of 5-lipoxygenase-activating protein(FLAP) in a mammal comprising administering to the mammal at least oncean effective amount of a compound having the structure of any of Formula(E), Formula (E-I), or Formula (E-II).

In a further or alternative embodiment, the “G” group (e.g. G₁, G₅, G₆,G₇) of any of Formula (E), Formula (E-I), or Formula (E-II), is anygroup that is used to tailor the physical and biological properties ofthe molecule. Such tailoring/modifications are achieved using groupswhich modulate acidity, basicity, lipophilicity, solubility and otherphysical properties of the molecule. The physical and biologicalproperties modulated by such modifications to “G” include, by way ofexample only, solubility, in vivo absorption, and in vivo metabolism. Inaddition, in vivo metabolism may include, by way of example only,controlling in vivo PK properties, off-target activities, potentialtoxicities associated with cypP450 interactions, drug-drug interactions,and the like. Further, modifications to “G” allow for the tailoring ofthe in vivo efficacy of the compound through the modulation of, by wayof example, specific and non-specific protein binding to plasma proteinsand lipids and tissue distribution in vivo. Additionally, suchtailoring/modifications to “G” allow for the design of compoundsselective for 5-lipoxygenase-activating protein over other proteins. Infurther or alternative embodiments, “G” is L₂₀-Q, wherein L₂₀ is anenzymatically cleavable linker and Q is a drug, or an affinity moiety.In further or alternative embodiments, the drug includes, by way ofexample only, leukotriene receptor antagonists and anti-inflammatoryagents. In further or alternative embodiments, the leukotriene receptorantagonists include, but are not limited to, CysLT1/CysLT2 dualantagonists and CysLT1 antagonists. In further or alternativeembodiments, the affinity moiety allows for site specific binding andinclude, but are not limited to, antibodies, antibody fragments, DNA,RNA, siRNA, and ligands.

In another aspect are methods for modulating, including reducing and/orinhibiting the activity of 5-lipoxygenase activating protein, directlyor indirectly, in a mammal comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of any of Formula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for modulating, including reducing and/orinhibiting, the activity of leukotrienes in a mammal, directly orindirectly, comprising administering to the mammal at least once aneffective amount of at least one compound having the structure of any ofFormula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for treating leukotriene-dependent orleukotriene mediated conditions or diseases, comprising administering tothe mammal at least once an effective amount of at least one compoundhaving the structure of any of Formula (E), Formula (E-I), or Formula(E-II).

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of any of Formula (E), Formula(E-I), or Formula (E-II).

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of any of Formula (E),Formula (E-I), or Formula (E-II). In a further embodiment of thisaspect, the respiratory disease is asthma. In a further embodiment ofthis aspect, the respiratory disease includes, but is not limited to,adult respiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,

In another aspect are methods for treating chronic obstructive pulmonarydisease comprising administering to the mammal at least once aneffective amount of at least one compound having the structure of any ofFormula (E), Formula (E-I), or Formula (E-II). In a further embodimentof this aspect, chronic obstructive pulmonary disease includes, but isnot limited to, chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis.

In another aspect are methods for preventing increased mucosal secretionand/or edema in a disease or condition comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of any of Formula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for treating vasoconstriction,atherosclerosis and its sequelae myocardial ischemia, myocardialinfarction, aortic aneurysm, vasculitis and stroke comprisingadministering to the mammal an effective amount of a compound having thestructure of any of Formula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for treating organ reperfusion injuryfollowing organ ischemia and/or endotoxic shock comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of any of Formula (E), Formula (E-I), or Formula(E-II).

In another aspect are methods for reducing the constriction of bloodvessels in a mammal comprising administering to the mammal at least oncean effective amount of at least one compound having the structure of anyof Formula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of any of Formula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte recruitmentcomprising administering to the mammal at least once an effective amountof at least one compound having the structure of any of Formula (E),Formula (E-I), or Formula (E-II).

A further aspect are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering to the mammal at least once aneffective amount of at least one compound having the structure of any ofFormula (B), Formula (E-I), or Formula (E-II).

In another aspect are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering to the mammal at least once aneffective amount of at least one having the structure of any of Formula(E), Formula (E-I), or Formula (E-II).

In another aspect are methods for treating CNS disorders comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of any of Formula (E), Formula(E-I), or Formula (E-II). CNS disorders include, but are not limited to,multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke,cerebral ischemia, retinal ischemia, post-surgical cognitivedysfunction, migraine, peripheral neuropathy/neuropathic pain, spinalcord injury, cerebral edema and head injury.

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of any of Formula (E), Formula(E-I), or Formula (E-II). The type of cancer may include, but is notlimited to, pancreatic cancer and other solid or hematological tumors.

In another aspect are methods for treating endotoxic shock and septicshock comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of any of Formula(E), Formula (E-I), or Formula (E-II).

In another aspect are methods for treating rheumatoid arthritis andosteoarthritis comprising administering to the mammal at least once aneffective amount of at least one compound having the structure of any ofFormula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for preventing increased GI diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of any of Formula (E),Formula (E-I), or Formula (E-II). Such diseases include, by way ofexample only, chronic gastritis, eosinophilic gastroenteritis, andgastric motor dysfunction.

A further aspect are methods for treating kidney diseases comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of any of Formula (E), Formula(E-I), or Formula (E-II). Such diseases include, by way of example only,glomerulonephritis, cyclosporine nephrotoxicity renal ischemiareperfusion.

In another aspect are methods for preventing or treating acute orchronic renal insufficiency comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of any of Formula (E), Formula (E-I), or Formula (E-II).

In another aspect are methods for treating type II diabetes comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of any of Formula (E), Formula(E-I), or Formula (E-II).

In another aspect are methods to diminish the inflammatory aspects ofacute infections within one or more solid organs or tissues such as thekidney with acute pyelonephritis.

In another aspect are methods for preventing or treating acute orchronic disorders involving recruitment or activation of eosinophilscomprising administering to the mammal at least once an effective amountof at least one compound described herein.

In another aspect are methods for preventing or treating acute orchronic erosive disease or motor dysfunction of the gastrointestinaltract caused by non-steroidal anti-inflammatory drugs (includingselective or non-selective cyclooxygenase-1 or -2 inhibitors) comprisingadministering to the mammal at least once an effective amount of atleast one compound described herein. A further aspect are methods forthe prevention or treatment of rejection or dysfunction in atransplanted organ or tissue comprising administering to the mammal atleast once an effective amount of at least one compound describedherein.

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound described herein. Such inflammatoryresponses of the skin include, by way of example, dermatitis, contactdermatitis, eczema, urticaria, rosacea, and scarring. In another aspectare methods for reducing psoriatic lesions in the skin, joints, or othertissues or organs, comprising administering to the mammal an effectiveamount of a first compound having the structure of any of Formula (E),Formula (E-I), or Formula (E-II).

A further aspect are methods for the treatment of cystitis, including,by way of example only, interstitial cystitis, comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of any of Formula (E), Formula (E-I), or Formula(E-II).

A further aspect are methods for the treatment of metabolic syndromessuch as Familial Mediterranean Fever comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of any of Formula (E), Formula (E-I), or Formula (E-II).

In a further aspect are methods to treat hepatorenal syndrome comprisingadministering to the mammal at least once an effective amount of atleast one compound described herein.

In another aspect is the use of a compound described herein, in themanufacture of a medicament for treating an inflammatory disease orcondition in an animal in which the activity of at least one leukotrieneprotein contributes to the pathology and/or symptoms of the disease orcondition. In one embodiment of this aspect, the leukotriene pathwayprotein is 5-lipoxygenase-activating protein (FLAP). In another orfurther embodiment of this aspect, the inflammatory disease orconditions are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in whichadministration is enteral, parenteral, or both, and wherein (a) theeffective amount of the compound is systemically administered to themammal; and/or (b) the effective amount of the compound is administeredorally to the mammal; and/or (c) the effective amount of the compound isintravenously administered to the mammal; and/or (d) the effectiveamount of the compound administered by inhalation; and/or (e) theeffective amount of the compound is administered by nasaladministration; or and/or (i) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically (dermal) to the mammal; and/or(h) the effective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal.

In any of the aforementioned aspects are further embodiments in whichthe mammal is a human, including embodiments wherein (a) the human hasan asthmatic condition or one or more other condition(s) selected fromthe group consisting of allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, or seasonal asthma, or chronic obstructivepulmonary disease, or pulmonary hypertension or interstitial lungfibrosis. In any of the aforementioned aspects are further embodimentsin which the mammal is an animal model for pulmonary inflammation,examples of which are provided herein.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredin a single dose; (ii) the time between multiple administrations isevery 6 hours; (iii) the compound is administered to the mammal every 8hours. In further or alternative embodiments, the method comprises adrug holiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. The length of the drug holiday can vary from 2 days to 1 year.

In any of the aforementioned aspects involving the treatment ofleukotriene dependent diseases or conditions are further embodimentscomprising administering at least one additional agent, each agent maybe administered in any order, including, by way of example, ananti-inflammatory agent, a different compound having the structure ofany of Formula (E), Formula (E-I), or Formula (E-II), a CysLT₁ receptorantagonist, or a CysLT₁/CysLT₂ dual receptor antagonist. In further oralternative embodiments, the CysLT₁ antagonist is selected frommontelukast (Singulair™:[1-[[1-[3-[2-[(7-chloro-2-quinolyl)]vinyl]phenyl]-3-[2-(1-hydroxy-1-methyl-ethyl)phenyl]-propyl]sulfanylmethyl]cyclopropyl]aceticacid), zafirlukast (Accolate™:3-[[2-methoxy-4-(o-tolylsulfonylcarbamoyl)phenyl]methyl]-1-methyl-1H-indol-5-yl]aminoformicacid cyclopentyl ester) or pranlukast (Onon™:4-oxo-8-[p-(4-phenylbutyloxy)benzoylamino]-2-tetrazol-5-yl)₄H-1-benzopyran)

In further or alternative embodiments, the anti-inflammatory agentincludes, but is not limited to, non-steroidal anti-inflammatory drugssuch as a cyclooxygenase inhibitor (COX-1 and/or COX-2), lipoxygenaseinhibitors and steroids such as prednisone or dexamethasone. In furtheror alternative embodiments, the anti-inflammatory agent is selected fromthe group consisting of Arthrotec®, Asacol, Auralgan®, Azulfidine,Daypro, etodolac, Ponstan, Salofalk, Solu-Medrol, aspirin, indomethacin(Indocin™), rofecoxib (Vioxx™), celecoxib (Celebrex™), valdecoxib(Bextra™), diclofenac, etodolac, ketoprofen, Lodine, Mobic, nabumetone,naproxen, piroxicam, Celestone, prednisone, Deltasone, or any genericequivalent thereof.

In any of the aforementioned aspects involving the treatment ofproliferative disorders, including cancer, are further embodimentscomprising administering at least one additional agent selected from thegroup consisting of alemtuzuab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguailine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase inhibitors such as irinotecanor topotecan, tyrosine kinase inhibitors such as gefinitinib orimatinib, or agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, granisetron/ondansetron/palonosetron,dronabinol.

In any of the aforementioned aspects involving the therapy oftransplanted organs or tissues or cells are further embodimentscomprising administering at least one additional agent selected from thegroup consisting of azathioprine, a corticosteroid, cyclophosphamide,cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin,tacrolimus, or thymoglobulin.

In any of the aforementioned aspects involving the therapy ofinterstitial cystitis are further embodiments comprising administeringat least one additional agent selected from dimethylsulfoxide,omalizumab, and pentosan polysulfate.

In any of the aforementioned aspects involving the therapy of disordersof bone are further embodiments comprising administering at least oneadditional agent selected from the group consisting of minerals,vitamins, bisphosphonates, anabolic steroids, parathyroid hormone oranalogs, and cathepsin K inhibitors dronabinol.

In any of the aforementioned aspects involving the prevention ortreatment of inflammation are further embodiments comprising: (a)monitoring inflammation in a mammal; (b) measuring bronchoconstrictionin a mammal; (c) measuring eosinophil and/or basophil and/or dendriticcell and/or neutrophil and/or monocyte and/or lymphocyte recruitment ina mammal; (d) monitoring mucosal secretion in a mammal; (e) measuringmucosal edema in a mammal; (e) measuring levels of LTB₄ in the calciumionophore-challenged blood of a mammal; (f) measuring levels of LTE₄ inthe urinary excretion of a mammal; or (g) identifying a patient bymeasuring leukotriene-driven inflammatory biomarkers such as LTB₄, LTC₄,Il-6, CRP, SAA, MPO, EPO, MCP-1, MIP-α, sICAMs, Il-4, Il-13.

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients byscreening for a leukotriene gene haplotype. In further or alternativeembodiments the leukotriene gene haplotype is a leukotriene pathwaygene, while in still further or alternative embodiments, the leukotrienegene haplotype is a 5-lipoxygenase-activating protein (FLAP) haplotype.

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients bymonitoring the patient for either:

-   -   i) at least one leukotriene related inflammatory biomarker; or    -   ii) at least one functional marker response to a leukotriene        modifying agent; or    -   iii) at least one leukotriene related inflammatory biomarker and        at least one functional marker response to a leukotriene        modifying agent.        In further or alternative embodiments, the leukotriene-related        inflammatory biomarkers are selected from the group consisting        of LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1,        MIP-α, sICAM, IL-6, IL-4, and IL-13, while in still further or        alternative embodiments, the functional marker response is        significant lung volume (FEV1).

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients byeither:

-   -   i) screening the patient for at least one leukotriene gene SNP        and/or haplotype including SNP's in intronic or exonic        locations; or    -   ii) monitoring the patient for at least one leukotriene related        inflammatory biomarker; or    -   ii) monitoring the patient for at least one functional marker        response to a leukotriene modifying agent        In further or alternative embodiments, the leukotriene gene SNP        or haplotype is a leukotriene pathway gene. In still further or        alternative embodiments, the leukotriene gene SNP or haplotype        is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype.        In further or alternative embodiments, the leukotriene-related        inflammatory biomarkers are selected from the group consisting        of LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1,        MIP-α, sICAM, IL-6, IL-4, and IL-13, while in still further or        alternative embodiments, the functional marker response is        significant lung volume (FEV1).

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients by atleast two of the following:

-   -   i) screening the patient for at least one leukotriene gene SNP        or haplotype;    -   ii) monitoring the patient for at least one leukotriene related        inflammatory biomarker;    -   ii) monitoring the patient for at least one functional marker        response to a leukotriene modifying agent.        In further or alternative embodiments, the leukotriene gene SNP        or haplotype is a leukotriene pathway gene. In still further or        alternative embodiments, the leukotriene gene SNP or haplotype        is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype.        In further or alternative embodiments, the leukotriene-related        inflammatory biomarkers are selected from the group consisting        of LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1,        MIP-α, sICAM, IL-6, IL-4, and IL-13, while in still further or        alternative embodiments, the functional marker response is        significant lung volume (FEV1).

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients by:

-   -   i) screening the patient for at least one leukotriene gene SNP        or haplotype; and    -   ii) monitoring the patient for at least one leukotriene related        inflammatory biomarker; and    -   ii) monitoring the patient for at least one functional marker        response to a leukotriene modifying agent.        In further or alternative embodiments, the leukotriene gene SNP        or haplotype is a leukotriene pathway gene. In still further or        alternative embodiments, the leukotriene gene SNP or haplotype        is a 5-lipoxygenase-activating protein (FLAP) SNP or haplotype.        In further or alternative embodiments, the leukotriene-related        inflammatory biomarkers are selected from the group consisting        of LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1,        MIP-α, sICAM, IL-6, IL-4, and IL-13, while in still further or        alternative embodiments, the functional marker response is        significant lung volume (FEV1).

In another aspect is the prevention or treatment ofleukotriene-dependent or leukotriene mediated diseases or conditionscomprising administering to a patient an effective amount of a FLAPmodulator, wherein the patients has been identified using informationobtained by:

-   -   i) screening the patient for at least one leukotriene gene SNP        or haplotype; and    -   ii) monitoring the patient for at least one leukotriene related        inflammatory biomarker; and    -   ii) monitoring the patient for at least one functional marker        response to a leukotriene modifying agent.        In further or alternative embodiments, the FLAP modulator is a        FLAP inhibitor. In further or alternative embodiments, the        leukotriene gene SNP or haplotype is a leukotriene pathway gene.        In still further or alternative embodiments, the leukotriene        gene SNP or haplotype is a 5-lipoxygenase-activating protein        (FLAP) SNP or haplotype. In further or alternative embodiments,        the leukotriene-related inflammatory biomarkers are selected        from the group consisting of LTB₄, cysteinyl leukotrienes, CRP,        SAA, MPO, EPO, MCP-1, MIP-α, sICAM, IL-6, IL-4, and IL-13, while        in still further or alternative embodiments, the functional        marker response is significant lung volume (FEV1). In further or        alternative embodiments, the information obtained from the three        diagnostic methods may be used in an algorithm in which the        information is analyzed to identify patients in need of        treatment with a FLAP modulator, the treatment regimen, and the        type of FLAP modulator used.

In any of the aforementioned aspects the leukotriene-dependent orleukotriene mediated diseases or conditions include, but are not limitedto, asthma, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, rhinitis, arthritis, allergy,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, and endotoxic shock.

Certain Chemical Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A(2000) and B (2001), Plenum Press, New York. Unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety may also be an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group consistingof at least two carbon atoms and at least one carbon-carbon double bond,and an “alkyne” moiety refers to a group consisting of at least twocarbon atoms and at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, may be branched, straightchain, or cyclic.

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupmay consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., upto and including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group could also be a “lower alkyl” having 1 to 5carbon atoms. The alkyl group of the compounds described herein may bedesignated as “C₁-C₄ alkyl” or similar designations. By way of exampleonly, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarybutyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from the group x=1, y=1 and x=−2, y=0. When x=2, thealkyl groups, taken together, can optionally form a cyclic ring system.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atomsC(R)═C—R, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH, —C(CH₃)═CH, —CH═CCH₃ and —C(CH₃)═CCH₃. Thealkenyl moiety may be branched, straight chain, or cyclic (in whichcase, it would also be known as a “cycloalkenyl” group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group, which may be the same or different.Non-limiting examples of an alkynyl group include —C≡CH, —C≡CH₃ and—C≡CCH₂CH₃. The “R” portion of the alkynyl moiety may be branched,straight chain, or cyclic.

An “amide” is a chemical moiety with formula —C(O)NHR or —NHC(O)R, whereR is selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). An amide may be an amino acid or a peptidemolecule attached to a compound of any of Formula (E), Formula (E-I), orFormula (E-II), thereby forming a prodrug. Any amine, or carboxyl sidechain on the compounds described herein can be amidified. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

The term “aromatic” or “aryl” refers to an aromatic group which has atleast one ring having a conjugated pi electron system and includes bothcarbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or “heteroaryl”or “heteroaromatic”) groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of carbon atoms) groups. The term “carbocyclic” refers to acompound which contains one or more covalently closed ring structures,and that the atoms forming the backbone of the ring are all carbonatoms. The term thus distinguishes carbocyclic from heterocyclic ringsin which the ring backbone contains at least one atom which is differentfrom carbon.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

A “cyano” group refers to a —CN group.

The term “cycloalkyl” refers to a monocyclic or polycyclic radical thatcontains only carbon and hydrogen, and may be saturated, partiallyunsaturated, or fully unsaturated. Cycloalkyl groups include groupshaving from 3 to 10 ring atoms. Illustrative examples of cycloalkylgroups include the following moieties:

and the like.

The term “ester” refers to a chemical moiety with formula COOR, where Ris selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any hydroxy, or carboxyl side chain on thecompounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety. The term “halo” or, alternatively, “halogen” means fluoro,chloro, bromo or iodo.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures that aresubstituted with one or more halo groups or with combinations thereof.The terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl andhaloalkoxy groups, respectively, in which the halo is fluorine.

The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl radicals and whichhave one or more skeletal chain atoms selected from an atom other thancarbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinationsthereof.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. The polycyclicheteroaryl group may be fused or non-fused. Illustrative examples ofheteroaryl groups include the following moieties:

and the like.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groupsinclude groups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a4-membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5-membered heterocyclic group is thiazolyl. An example of a6-membered heterocyclic group is pyridyl, and an example of a10-membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one.

A “heteroalicyclic” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur, i.e.,non-aromatic heterocycle groups. The radicals may be fused with an arylor heteroaryl. Illustrative examples of heterocycloalkyl groups, alsoreferred to as heteroalicyclic groups, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

A “mercaptyl” group refers to a (alkyl)S— group.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “sulfinyl” group refers to a —S(═O)—R, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon)

A “sulfonyl” group refers to a —S(═O)₂—R, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon)

A “thiocyanato” group refers to a —CNS group.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone,arylsulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanato,thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl,and amino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. By way of example an optionalsubstituents may be L_(s)R_(s), wherein each L_(s) is independentlyselected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NH—,—NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—,-(substituted or unsubstituted C₁-C₆ alkyl), or -(substituted orunsubstituted C₂-C₆ alkenyl); and each R_(s) is independently selectedfrom H, (substituted or unsubstituted lower alkyl), (substituted orunsubstituted lower cycloalkyl), heteroaryl, or heteroalkyl. Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art as, for example, theseparation of stereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Certain Pharmaceutical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator whichenhances the activity of another molecule or the activity of a receptorsite.

The term “antagonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme inhibitor, or a hormone modulator, whichdiminishes, or prevents the action of another molecule or the activityof a receptor site.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

The term “bone disease,’ as used herein, refers to a disease orcondition of the bone, including, but not limited to, inappropriate boneremodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, andPaget's disease [Garcia, “Leukotriene B4 stimulates osteoclastic boneresorption both in intro and in vivo”, J Bone Miner Res. 1996;11:1619-27].

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia; atherosclerosis and its sequelae; angina; myocardialischemia; myocardial infarction; cardiac or vascular aneurysm;vasculitis, stroke; peripheral obstructive arteriopathy of a limb, anorgan, or a tissue; reperfusion injury following ischemia of the brain,heart or other organ or tissue; endotoxic, surgical, or traumatic shock;hypertension, valvular heart disease, heart failure, abnormal bloodpressure; shock; vasoconstriction (including that associated withmigraines); vascular abnormality, inflammation, insufficiency limited toa single organ or tissue. [Lotzer K et al., “The 5-lipoxygenase pathwayin arterial wall biology and atherosclerosis”, Biochim Biophys Acta2005; 1736:30-7; Helgadottir A et al., “The gene encoding 5-lipoxygenaseactivating protein confers risk of myocardial infarction and stroke’,Nat. Genet. 2004 March; 36(3):233-9. Epub 2004 Feb. 8; [Heise C E, EvansJ F et al., “Characterization of the human cysteinyl leukotriene 2receptor”, J Biol Chem. 2000 Sep. 29; 275(39):30531-6].

The term “cancer,’ as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematological tumors (such as the leukemias) [Ding X Z et al., “Anovel anti-pancreatic cancer agent, LY293111”, Anticancer Drugs. 2005June; 16(5):467-73. Review; Chen X et al., “Overexpression of5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitoryeffects of zileuton and celecoxib on carcinogenesis”, Clin Cancer Res.2004 Oct. 1; 10(19):6703-9].

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “dermatological disorder,” as used herein refers to a skindisorder. Such dermatological disorders include, but are not limited to,proliferative or inflammatory disorders of the skin such as, atopicdermatitis, bullous disorders, collagenoses, contact dermatitis eczema,Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria [Wedi B etal., “Pathophysiological role of leukotrienes in dermatologicaldiseases: potential therapeutic implications”, BioDrugs. 2001;15(11):729-43].

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “enzymatically cleavable linker,” as used herein refers tounstable or degradable linkages which may be degraded by one or moreenzymes.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that follow acute or chronic inflammation and are associatedwith the abnormal accumulation of cells and/or collagen and include butare not limited to fibrosis of individual organs or tissues such as theheart, kidney, joints, lung, or skin, and includes such disorders asidiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis[Charbeneau R P et al., “Eicosanoids: mediators and therapeutic targetsin fibrotic lung disease”, Clin Sci (Lond). 2005 June; 108(6):479-91].

The term “iatrogenic” means a leukotriene-dependent orleukotriene-mediated condition, disorder, or disease created or worsenedby medical or surgical therapy.

The term “inflammatory disorders” refers to those diseases or conditionsthat are characterized by one or more of the signs of pain (dolor, fromthe generation of noxious substances and the stimulation of nerves),heat (calor, from vasodilatation), redness (rubor, from vasodilatationand increased blood flow), swelling (tumor, from excessive inflow orrestricted outflow of fluid), and loss of function (functio laesa, whichmay be partial or complete, temporary or permanent). Inflammation takesmany forms and includes, but is not limited to, inflammation that is oneor more of the following: acute, adhesive, atrophic, catarrhal, chronic,cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing,focal, granulomatous, hyperplastic, hypertrophic, interstitial,metastatic, necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative. Inflammatory disorders further include, without beinglimited to those affecting the blood vessels (polyarteritis, temporarlarteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive,rheumatoid, Reiter's); gastrointestinal tract (Disease); skin(dermatitis); or multiple organs and tissues (systemic lupuserythematosus) [Harrison's Principles of Internal Medicine, 16^(th)Edition, Kasper D L, et al, Editors; McGraw-Hill, publishers].

The term “interstitial cystitis” refers to a disorder characterized bylower abdominal discomfort, frequent and sometimes painful urinationthat is not caused by anatomical abnormalites, infection, toxins, traumaor tumors [Bouchelouche K et al., “The cysteinyl leukotrine D4 receptorantagonst montelukast for the treatment of interstitial cystitis”, JUrol 2001; 166:1734].

The term “leukotriene-driven mediators,” as used herein, refers tomolecules able to be produced in a patient that may result fromexcessive production of leukotriene stimulation of cells, such as, byway of example only, LTB₄, LTC₄, LTE₄, cysteinyl leuktorienes, monocyteinflammatory protein (MIP-1α), interleukin-8 (IL-8), interleukin-4(IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein(MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM),myeloperoxidase (MPO), eosinophil peroxidase (EPO), and generalinflammation molecules such as interleukin-6 (II-6), C-reactive protein(CRP), and serum amyloid A protein (SAA).

The term “leukotriene-related mediators,” as used herein, refers tomolecules able to be produced in a patient that may result fromexcessive production of leukotriene stimulation of cells, such as, byway of example only, LTB₄, LTC₄, LTE₄, cysteinyl leuktorienes, monocyteinflammatory protein (MIP-1α), interleukin-8 (IL-8), interleukin-4(IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein(MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM),myeloperoxidase (MPO), eosinophil peroxidase (EPO), and generalinflammation molecules such as interleukin-6 (Il-6), C-reactive protein(CRP), and serum amyloid A protein (SAA).

The term “leukotriene-dependent”, as used herein, refers to conditionsor disorders that would not occur, or would not occur to the sameextent, in the absence of one or more leukotrienes.

The term “leukotriene-mediated”, as used herein, refers to refers toconditions or disorders that might occur in the absence of leukotrienesbut can occur in the presence of one or more leukotrienes.

The term “leukotriene-responsive patient,” as used herein, refers to apatient who has been identified by either genotyping of FLAP haplotypes,or genotyping of one or more other genes in the leukotriene pathwayand/or, by phenotyping of patients either by previous positive clinicalresponse to another leukotriene modulator, including, by way of exampleonly, zileuton (Zyflo™), montelukast (Singulair™), pranlukast (Onon™),zafirlukast (Accolate™), and/or by their profile of leukotriene-drivenmediators that indicate excessive leukotriene stimulation ofinflammatory cells, as likely to respond favorably to leukotrienemodulator therapy.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulfhydryl groups. Further information on metabolism may be obtainedfrom The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill(1996). Metabolites of the compounds disclosed herein can be identifiedeither by administration of compounds to a host and analysis of tissuesamples from the host, or by incubation of compounds with hepatic cellsin vitro and analysis of the resulting compounds. Both methods are wellknown in the art.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist and anantagonist.

The terms “neurogenerative disease” or “nervous system disorder,” asused herein, refers to conditions that alter the structure or functionof the brain, spinal cord or peripheral nervous system, including butnot limited to Alzheimer's Disease, cerebral edema, cerebral ischemia,multiple sclerosis, neuropathies, Parkinson's Disease, those found afterblunt or surgical trauma (including post-surgical cognitive dysfunctionand spinal cord or brain stem injury), as well as the neurologicalaspects of disorders such as degenerative disk disease and sciatica. Theacronym “CNS” refers to disorders of the central nervous system, i.e.,brain and spinal cord [Sugaya K, et al., “New anti-inflammatorytreatment strategy in Alzheimer's disease”, Jpn J Pharmacol. 2000February; 82(2):85-94; Yu G L, et al., “Montelukast, a cysteinylleukotriene receptor-1 antagonist, dose- and time-dependently protectsagainst focal cerebral ischemia in mice”, Pharmacology. 2005 January;73(1):31-40. Epub 2004 Sep. 27; [Zhang W P, et al., “Neuroprotectiveeffect of ONO-1078, a leukotriene receptor antagonist, on focal cerebralischemia in rats’, Acta Pharmacol Sin. 2002 October; 23(10):871-7].

The terms “ocular disease” or “ophthalmic disease,” as used herein,refer to diseases which affect the eye or eyes and potentially thesurrounding tissues as well. Ocular or ophthalmic diseases include, butare not limited to, conjunctivitis, retinitis, scleritis, uveitis,allergic conjunctivitis, vernal conjunctivitis, papillary conjunctivitis[Toriyama S., “Effects of leukotriene B4 receptor antagonist onexperimental autoimmune uveoretinitis in rats”, Nippon Ganka GakkaiZasshi. 2000 June; 104(6):396-40; [Chen F, et al., “Treatment of Santigen uveoretinitis with lipoxygenase and cyclo-oxygenase inhibitors”,Ophthalmic Res. 1991; 23(2):84-91].

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutically acceptable salts may beobtained by reacting a compound described herein, with acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticallyacceptable salts may also be obtained by reacting a compound describedherein, with a base to form a salt such as an ammonium salt, an alkalimetal salt, such as a sodium or a potassium salt, an alkaline earthmetal salt, such as a calcium or a magnesium salt, a salt of organicbases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts with amino acids such asarginine, lysine, and the like, or by other methods known in the art

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound of any of Formula (E), Formula (E-I), or Formula (E-II),which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety.

The term “respiratory disease” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, trachea, bronchi, and lungs. Respiratory diseasesinclude, but are not limited to, asthma, adult respiratory distresssyndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child-onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia [Evans J F, “The Cysteinyl Leukotriene (CysLT)Pathway in Allergic Rhinitis”, Allergology International 2005; 54:187-90); Kemp J P., “Leukotriene receptor antagonists for the treatmentof asthma”, IDrugs. 2000 April; 3(4):430-41; Riccioni G, et al., “Effectof the two different leukotriene receptor antagonists, montelukast andzafirlukast, on quality of life: a 12-week randomized study”, AllergyAsthma Proc. 2004 November-December; 25(6):445-8].

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the inventionwill become apparent to those skilled in the art from this detaileddescription. All references cited herein, including patents, patentapplications, and publications, are hereby incorporated by reference intheir entirety.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 2 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 3 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 4 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 5 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 6 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 7 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 8 presents illustrative examples of compounds described herein.

FIG. 9 presents illustrative examples of compounds described herein.

FIG. 10 presents illustrative examples of compounds described herein.

FIG. 11 presents illustrative examples of compounds described herein.

FIG. 12 present an illustrative scheme for the treatment of patientsusing the compounds and methods described herein.

FIG. 13 present an illustrative scheme for the treatment of patientsusing the compounds and methods described herein.

FIG. 14 present an illustrative scheme for the treatment of patientsusing the compounds and methods described herein.

DETAILED DESCRIPTION OF THE INVENTION Illustrative Biological Activity

Leukotrienes (LTs) are potent contractile and inflammatory mediatorsproduced by release of arachidonic acid from cell membranes andconversion to leukotrienes by the action of 5-lipoxygenase,5-lipoxygenase-activating protein, LTA₄ hydrolase and LTC₄ synthase. Theleukotriene synthesis pathway, or 5-lipoxygenase pathway, involves aseries of enzymatic reactions in which arachidonic acid is converted toleukotriene LTB₄, or the cysteinyl leukotrienes, LTC₄, LTD₄, and LTE₄.The pathway occurs mainly at the nuclear envelope and has beendescribed. See, e.g., Wood, J W et al, J. Exp. Med., 178: 1935-1946,1993; Peters-Golden, Am. J. Respir. Crit. Care Med. 157:S227-S232, 1998;Drazen, et al., ed. Five-Lipoxygenase Products in Asthma, Lung Biologyin Health and Disease Series, Vol. 120, Chs. 1, 2, and 7, Marcel Dekker,Inc. NY, 1998. Protein components dedicated to the leukotriene synthesispathway include a 5-lipoxygenase (5-LO), a 5-lipoxygenase-activatingprotein, a LTA₄ hydrolase, and a LTC₄ synthase. The synthesis ofleukotrienes has been described in the literature, e.g., by Samuelssonet al, Science, 220, 568-575, 1983; Peters-Golden, “Cell Biology of the5-Lipoxygenase Pathway” Am J Respir Crit. Care Med 157:S227-S232 (1998).Leukotrienes are synthesized directly from arachidonic acid by differentcells including cosinophils, neutrophils, basophils, lymphocytes,macrophages, monocytes and mast cells. Excess LTA₄, for example from anactivated neutrophil, may enter a cell by a transcellular pathway. Mostcells in the body have LTA₄ hydrolase so can produce LTB₄. Platelets andendothelial cells have LTC₄ synthase, so can make LTC₄ when presentedwith LTA₄ by a transcellular pathway.

Arachidonic acid is a polyunsaturated fatty acid and is present mainlyin the membranes of the body's cells. Upon presentation of inflammatorystimuli from the exterior of the cell, calcium is released and binds tophospholipase A₂ (PLA2) and 5-LO. Cell activation results in thetranslocation of PLA₂ and 5-LO from the cytoplasm to the endoplasmicreticulum and/or nuclear membranes, where in the presence of FLAP, thereleased arachidonic acid is converted via a 5-HPETE intermediate to theepoxide LTA₄. Depending on the cell type, the LTA₄ may be immediatelyconverted to LTC₄ by the nuclear-bound LTC₄ synthase or to LTB₄ by theaction of cytosolic LTA₄ hydrolase. LTB₄ is exported from cells by an asyet uncharacterized transporter and may activate other cells, or thecell it was made in, via high affinity binding to one of two Gprotein-coupled receptors (GPCRs), namely BLT₁R or BLT₂R. LTC₄ isexported to the blood via the MRP-1 anion pump and rapidly converted toLTD₄ by the action of γ-glutamyl transpeptidase and LTD₄ is thenconverted to LTE₄ by the action of dipeptidases. LTC₄, LTD₄ and LTE₄ arecollectively referred to as the cysteinyl leukotrienes (or previously asslow reacting substance of anaphylaxis, SRS-A). The cysteinylleukotrienes activate other cells, or the cells they are made in, viahigh affinity binding to one of two GPCRs, namely CysLT₁R or CysLT₂R.CysLT₁ receptors are found in the human airway eosinophils, neutrophils,macrophages, mast cells, B-lymphocytes and smooth muscle and inducebronchoconstriction. Zhu et al, Am J Respir Cell Mol Biol Epub Aug. 25(2005). CysLT₂ receptors are located in human airway eosinophils,macrophages, mast cells the human pulmonary vasculature Figueroa et al,Clin Exp Allergy 33:1380-1388 (2003).

Involvement of Leukotrienes in Diseases or Conditions

The involvement of leukotrienes in disease is described in detail in theliterature. See e.g., by Busse, Clin. Exp. Allergy 26:868-79, 1996;O'Byrne, Chest 111(Supp. 2): 27S-34S, 1977; Sheftell, F. D., et al.,Headache, 40:158-163, 2000; Klickstein et al., J. Clin. Invest.,66:1166-1170, 1950; Davidson et al., Ann. Rheun. Dis., 42:677-679, 1983Leukotrienes produce marked inflammatory responses in human skin.Evidence for the involvement of leukotrienes in a human disease is foundin psoriasis, in which leukotrienes have been detected in psoriaticlesions (Kragballe et al., Arch. Dermatol., 119:548-552, 1983).

For example, inflammatory responses have been suggested to reflect threetypes of changes in the local blood vessels. The primary change is anincrease in vascular diameter, which results in an increase in localblood flow and leads to an increased temperature, redness and areduction in the velocity of blood flow, especially along the surfacesof small blood vessels. The second change is the activation ofendothelial cells lining the blood vessel to express adhesion moleculesthat promote the binding of circulating leukocytes. The combination ofslowed blood flow and induced adhesion molecules allows leukocytes toattach to the endothelium and migrate into the tissues, a process knownas extravasation. These changes are initiated by cytokines andleukotrienes produced by activated macrophages. Once inflammation hasbegun, the first cells attracted to the site of infection are generallyneutrophils. They are followed by monocytes, which differentiate intomore tissue macrophages. In the latter stages of inflammation, otherleukocytes, such as eosinophils and lymphocytes also enter the infectedsite. The third major change in the local blood vessels is an increasein vascular permeability. Instead of being tightly joined together, theendothelial cells lining the blood vessel walls become separated,leading to exit of fluid and proteins from the blood and their localaccumulation in the tissue. (See Janeway, et al., Immunobiology: theimmune system in health and disease, 5th ed., Garland Publishing, NewYork, 2001)

LTB₄ produces-relatively weak contractions of isolated trachea and lungparenchyma, and these contractions are blocked in part by inhibitors ofcyclooxygenase, suggesting that the contraction are secondary to therelease of prostaglandins. However, LTB₄ has been shown to be a potentchemotactic agent for eosinophils and progenitors of mast cells and theLTB₄ receptor BLT1−/− knockout mouse is protected from eosinophilicinflammation and T-cell mediated allergic airway hyperreactivity.Miyahara et al. J Immunol 174:4979-4784; (Weller et al. J Exp Med201:1961-1971 (2005).

Leukotrienes C₄ and D₄ are potent smooth muscle contractile agents,promoting bronchoconstriction in a variety of species, including humans(Dahlen et al., Nature, 288:484-486, 1980). These compounds haveprofound hemodynamic effects, constricting coronary blood vessels, andresulting in a reduction of cardiac output efficiency (Marone et al., inBiology of Leukotrienes, ed. By R. Levi and R. D. Krell, Ann. New YorkAcad. Sci. 524:321-333, 1988). Leukotrienes also act asvasoconstrictors, however, marked differences exist for differentvascular beds. There are reports suggesting that leukotrienes contributeto cardiac reperfusion injury following myocardial ischemia (Barst andMullane, Eur. J. Pharmacol., 114: 383-387, 1985; Sasaki et al.,Cardiovasc. Res., 22: 142-148, 1988). LTC₄ and LTD₄ directly increasevascular permeability probably by promoting retraction of capillaryendothelial cells via activation of the CysLT₂ receptor and possiblyother as yet undefined CysLT receptors [Lotzer et al. Arterioscler TrombVasc Biol 23: e32-36. (2003)]. LTB₄ enhances atherosclerotic progressionin two atherosclerotic mouse models, namely low density receptorlipoprotein receptor deficient (LDLr−/−) and apolipoprotein E-deficient(ApoE−/−) mice (Aiello et al, Arterioscler Thromb Vasc Biol 22:443-449(2002); Subbarao et al, Arterioscler Thromb Vasc Biol 24:369-375 (2004);Heller et al. Circulation 112:578-586 (2005). LTB₄ has also been shownto increase human monocyte chemoattractant protein (MCP-1) a knownenhancer of atherosclerotic progression (fluang et al. AteriosclerThromb Vasc Biol 24:1783-1788 (2004).

The role of FLAP in the leukotriene synthesis pathway is significantbecause FLAP in concert with 5-lipoxygenase performs the first step inthe pathway for the synthesis of leukotrienes. Therefore the leukotrienesynthesis pathway provides a number of targets for compounds useful inthe treatment of leukotriene-dependent or leukotriene mediated diseasesor conditions, including, by way of example, vascular and inflammatorydisorders, proliferative diseases, and non-cancerous disorders.

Leukotriene-dependent or leukotriene mediated conditions treated usingthe methods, compounds, pharmaceutical compositions and medicamentsdescribed herein, include, but are not limited to, bone diseases anddisorder, cardiovascular diseases and disorders, inflammatory diseasesand disorders, dermatological diseases and disorders, ocular diseasesand disorders, cancer and other proliferative diseases and disorders,respiratory diseases and disorder, and non-cancerous disorders.

Treatment Options

Leukotrienes are known to contribute to the inflammation of the airwaysof patients with asthma. CysLT₁ receptor antagonists such as montelukast(Singulair™) have been shown to be efficacious in asthma and allergicrhinitis (Reiss et al. Arch Intern Med 158:1213-1220 (1998); Phillip etal. Clin Exp Allergy 32:1020-1028 (2002)]. CysLT₁R antagonistspranlukast (Onon™) and zafirlukast (Accolate™) have also been shown tobe efficacious in asthma.

A number of drugs have been designed to inhibit leukotriene formation,including the 5-lipoxygenase inhibitor zileuton (Zyflo™) that has shownefficacy in asthma, Israel et al. Ann Intern Med 119:1059-1066 (1993).The 5-lipoxygenase inhibitor ZD2138 showed efficacy in inhibiting thefall of FEV1 resulting from aspirin-induced asthma, Nasser et al,Thorax, 49; 749-756 (1994). The following leukotriene synthesisinhibitors have shown efficacy in asthma: MK-0591, a specific inhibitorof 5-lipoxygenase-activating protein (FLAP), Brideau, et al., Ca. J.Physiol. Pharmacol. 70:799-807 (1992)., MK-886, a specific inhibitor of5-lipoxygenase-activating protein (FLAP), Friedman et al. Am Rev RespirDis., 147: 839-844 (1993), and BAY X1005, a specific inhibitor of5-lipoxygenase-activating protein (FLAP), Fructmann et al, AgentsActions 38: 188-195 (1993).

FLAP inhibition will decrease LTB₄ from monocytes, neutrophils and othercells involved in vascular inflammation and thereby decreaseatherosclerotic progression. The FLAP inhibitor MK-886 has been shown todecrease the postangioplasty vasoconstrictive response in a porcinecarotid injury model Provost et al. Brit J Pharmacol 123: 251-258(1998). MK-886 has also been shown to suppress femoral artery intimalhyperplasia in a rat photochemical model of endothelial injury Kondo etal. Thromb Haemost 79:635-639 (1998). The 5-lipoxygenase inhibitorzileuton has been shown to reduce renal ischemia in a mouse model,Nimesh et al. Mol Pharm 66:220-227 (2004).

FLAP modulators have been used for the treatment of a variety ofdiseases or conditions, including, by way of example only, (i)inflammation (see e.g. Leff A R et al., “Discovery of leukotrienes andthe development of antileukotriene agents”, Ann Allergy Asthma Immunol2001; 86 (Suppl 1)₄₋₈; Riccioni G, et al., “Advances in therapy withantileukotriene drugs”, Ann Clin Lab Sci. 2004, 34(4):379-870; (ii)respiratory diseases including asthma, adult respiratory distresssyndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child-onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma (see e.g. Riccioni et al, Ann.Clin. Lab. Sci., v34, 379-387 (2004)); (iii) chronic obstructivepulmonary disease, including chronic bronchitis or emphysema, pulmonaryhypertension, interstitial lung fibrosis and/or airway inflammation andcystic fibrosis (see e.g. Kostikas K et al., “Leukotriene V4 in exhaledbreath condensate and sputum supernatant in patients with COPD andasthma”, Chest 2004; 127:1553-9); (iv) increased mucosal secretionand/or edema in a disease or condition (see e.g. Shahab R et al.,“Prostaglandins, leukotrienes, and perennial rhinitis”, J LaryngolOtol., 2004; 118; 500-7); (v) vasoconstriction, atherosclerosis and itssequelae myocardial ischemia, myocardial infarction, aortic aneurysm,vasculitis and stroke (see e.g. Jala et al, Trends in Immunol., v25,315-322 (2004) and Mehrabian et al, Curr. Opin. Lipidol., v14, 447-457(2003)); (vi) reducing organ reperfusion injury following organ ischemiaand/or endotoxic shock (see e.g. Matsui N, et al., “Protective effect ofthe 5-lipoxygenase inhibitor ardisiaquinone A on hepaticischemia-reperfusion injury in rats”, Planta Med. 2005 August;71(8):717-20); (vii) reducing the constriction of blood vessels (seee.g. Stanke-Labesque F et al., “Inhibition of leukotriene synthesis withMK-886 prevents a rise in blood pressure and reducesnoradrenaline-evoked contraction in L-NAME-treated rats”, Br J.Pharmacol. 2003 September; 140(1): 186-94); (viii) lowering orpreventing an increase in blood pressure (see e.g. Stanke-Labesque F etal., “Inhibition of leukotriene synthesis with MK-886 prevents a rise inblood pressure and reduces noradrenaline-evoked contraction inL-NAME-treated rats”, Br J Pharmacol. 2003 September; 140(1): 186-94,and Walch L, et al., “Pharmacological evidence for a novelcysteinyl-leukotriene receptor subtype in human pulmonary artery smoothmuscle”, Br J Pharmacol. 2002 December; 137(8):1339-45); (ix) preventingeosinophil and/or basophil and/or dendritic cell and/or neutrophiland/or monocyte recruitment (see e.g. Miyahara N, et al., “LeukotrieneB4 receptor-1 is essential for allergen-mediated recruitment of CD8+ Tcells and airway hyperresponsiveness”, Immunol. 2005 Apr. 15;174(8):4979-84); (x) abnormal bone remodeling, loss or gain, includingosteopenia, osteoporosis, Paget's disease, cancer and other diseases(see e.g. Anderson G I, et al., “Inhibition of leukotriene function canmodulate particulate-induced changes in bone cell differentiation andactivity”, Biomed Mater Res. 2001; 58(4):406-140; (xi) ocularinflammation and allergic conjunctivitis, vernal keratoconjunctivitis,and papillary conjunctivitis (see e.g. Lambiase et al, Arch. Opthalmol.,vi 21, 615-620 (2003)); (xii) CNS disorders, including, but are notlimited to, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, stroke, cerebral ischemia, retinal ischemia, post-surgicalcognitive dysfunction, migraine (see e.g. de Souza Carvalho D, et al.,“Asthma plus migraine in childhood and adolescence: prophylacticbenefits with leukotriene receptor antagonist”, Headache. 2002November-December; 42(10): 1044-7; Sheftell F, et al., “Montelukast inthe prophylaxis of migraine: a potential role for leukotrienemodifiers”, Headache. 2000 February; 40(2):158-63); (xiii) peripheralneuropathy/neuropathic pain, spinal cord injury (see e.g. Akpek E A, etal., “A study of adenosine treatment in experimental acute spinal cordinjury. Effect on arachidonic acid metabolites”, Spine. 1999 January.15; 24(2): 128-32), cerebral edema and head injury; (xiv) cancer,including, but is not limited to, pancreatic cancer and other solid orhematological tumors, (see e.g. Poff and Balazy, Curr. Drug TargetsInflamm. Allergy, v3, 19-33 (2004) and Steele et al, Cancer Epidemiology& Prevention, v8, 467-483 (1999); (xv) endotoxic shock and septic shock(see e.g. Leite M S, et al., “Mechanisms of increased survival afterlipopolysaccharide-induced endotoxic shock in mice consuming oliveoil-enriched diet”, Shock. 2005 February; 23(2):173-8); (xvi) rheumatoidarthritis and osteoarthritis (see e.g. Alten R, et al., “Inhibition ofleukotriene B₄-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a newlong acting LTB₄ receptor antagonist, in patients with rheumatoidarthritis”, Ann Rheum Dis. 2004 February; 63(2): 170-6); (xvii)preventing increased GI diseases, including, by way of example only,chronic gastritis, eosinophilic gastroenteritis, and gastric motordysfunction, (see e.g. Gyomber et al, J Gastroenterol Hepatol., v11,922-927 (1996); Quack I et al BMC Gastroenterol v18,24 (2005); CuzzocreaS, et al., “5-Lipoxygenase modulates colitis through the regulation ofadhesion molecule expression and neutrophil migration”, Lab Invest. 2005June; 85(6):808-22); (xviii) kidney diseases, including, by way ofexample only, glomerulonephritis, cyclosporine nephrotoxicity renalischemia reperfusion. (see e.g. Guasch et al Kidney Int., v56, 261-267;Butterly et al, v 57, 2586-2593 (2000); Guasch A et al. “MK-591 acutelyrestores glomerular size selectivity and reduces proteinuria in humanglomerulonephritis”, Kidney Int. 1999; 56:261-7; Butterly D W et al. “Arole for leukotrienes in cyclosporine nephrotoxicity”, Kidney Int. 2000;57:2586-93); (xix) preventing or treating acute or chronic renalinsufficiency (see e.g. Maccarrone M, et al., “Activation of5-lipoxygenase and related cell membrane lipoperoxidation inhemodialysis patients”, J Am Soc Nephrol. 1999; 10:1991-6); (xx) type IIdiabetes (see e.g. Valdivielso et al, v6, 85-94 (2003); (xxi) diminishthe inflammatory aspects of acute infections within one or more solidorgans or tissues such as the kidney with acute pyelonephritis (see e.g.Tardif M, et al., L-651,392, “A potent leukotriene inhibitor, controlsinflammatory process in Escherichia coli pyelonephritis”, AntimicrobAgents Chemother. 1994 July; 38(7):1555-60); (xxii) preventing ortreating acute or chronic disorders involving recruitment or activationof eosinophils (see e.g. Quack I, et al. “Eosinophilic gastroenteritisin a young girl—long term remission under montelukast”, BMCGastroenterol., 2005; 5:24; (xxiii) preventing or treating acute orchronic erosive disease or motor dysfunction of the gastrointestinaltract caused by non-steroidal anti-inflammatory drugs (includingselective or non-selective cyclooxygenase-1 or -2 inhibitors) (see e.g.Marusova I B, et al., “Potential gastroprotective effect of a CysLT1receptor blocker sodium montelukast in aspirin-induced lesions of therat stomach mucosa”, Eksp Klin Farmakol, 2002; 65:16-8 and Gyomber E, etal., “Effect of lipoxygenase inhibitors and leukotriene antagonists onacute and chronic gastric haemorrhagic mucosal lesions in ulcer modelsin the rat”, J Gastroenterol. Hepatol., 1996, 11, 922-7) and Martin Stet al., “Gastric motor dysfunction: is eosinophilic mural gastritis acausative factor?”, Eur J Gastroenterol. Hepatol., 2005, 17:983-6;(xxiv) treating type II diabetes (see e.g. Valdivielso J M, et al.,“Inhibition of 5-lipoxygenase activating protein decreases proteinuriain diabetic rats”, J Nephrol. 2003 January-February; 16(1):85-94;Parlapiano C, et al., “The relationship between glaciated hemoglobin andpolymorphonuclear leukocyte leukotriene B4 release in people withdiabetes mellitus”, Diabetes Res Clin Pract. 1999 October; 46(1):43-5;(xxv) treatment of metabolic syndromes, including, by way of exampleonly, Familial Mediterranean Fever (see e.g. Bentancur A G, et al.,“Urine leukotriene B4 in familial Mediterranean fever”, Clin ExpRheumatol. 2004 July-August; 22(4 Suppl 34):S56-8; and (xxvi) treathepatorenal syndrome (see e.g. Capella G L., “Anti-leukotriene drugs inthe prevention and treatment of hepatorenal syndrome”, ProstaglandinsLeukot Essent Fatty Acids. 2003 April; 68(4):263-5].

Several inhibitors of FLAP have been described (Gillard et al, Can. J.Physiol. Pharmacol., 67, 456-464, 1989; Evans et al, MolecularPharmacol., 40, 22-27, 1991; Brideau et al, Can. J. Physiol. Pharmacol.,Musser et al, J. Med. Chem., 35, 2501-2524, 1992; Steinhilber, Curr.Med. Chem. 6(1):71-85, 1999; Riendeau, Bioorg Med Chem. Lett.,15(14):3352-5, 2005; Flamand, et al., Mol. Pharmacol. 62(2):250-6, 2002;Folco, et al., Am. J. Respir. Crit. Care Med. 161(2 Pt 2):S112-6, 2000;Hakonarson, JAMA, 293(18):2245-56, 2005).

Identification of Leukotriene Synthesis Pathway Inhibitors

The development and testing of novel FLAP inhibitors which are effectiveeither alone or in combination with other drugs, and which result inminimal negative side effects would be beneficial for treatingleukotriene-dependent or leukotriene mediated diseases or conditions.Inhibitors of the leukotriene synthesis pathway described herein maytarget any step of the pathway to prevent or reduce the formation ofleukotrienes. Such leukotriene synthesis inhibitors can, by way ofexample, inhibit at the level of FLAP, or 5-LO, thus minimizing theformation of various products in the leukotriene pathway, therebydecreasing the amounts of such compounds available in the cell.Leukotriene synthesis inhibitors can be identified based on theirability to bind to proteins in the leukotriene synthesis pathway. Forexample, FLAP inhibitors can be identified based on their binding toFLAP.

Compounds Compounds of Formula (E), Formula (E-I) and Formula (E-II):

Compounds of Formula (E), Formula (E-I), and Formula (E-II),pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides,pharmaceutically active metabolites, pharmaceutically acceptableprodrugs, and pharmaceutically acceptable solvates thereof, antagonizeor inhibit FLAP and may be used to treat patients suffering fromleukotriene-dependent or leukotriene mediated conditions or diseases,including, but not limited to, asthma, myocardial infarction, cancer,and inflammatory conditions.

Formula (E-I) is as follows:

wherein,

-   -   Z is selected from N(R₁), S(O)_(m), CR₁═CR₁, —C≡C—,        C(R₁)₂[C(R₂)₂]_(n), [C(R₂)₂]_(n)C(R₁)₂O, OC(R₁)₂[C(R₂)₂]_(n),        [C(R₂)₂]_(n)C(R₁)₂S(O)_(m), S(O)_(m)C(R₁)₂[C(R₂)₂]_(n),        [C(R₂)₂]_(n)C(R₁)₂NR₁, NR₁C(R₁)₂[C(R₂)₂]_(n),        [C(R₂)₂]O[C(R₁)₂]_(n), [C(R₁)₂]O[C(R₂)₂]_(n), —C(O)NR₂—,        —NR₂C(O)—, —NR₂C(O)O—, —OC(O)NR₂—, —S(O)₂NR₂—, —CR₁═N—N—,        NR₂C(O)NR₂—, —OC(O)O—, S(O)₂NR₂, or —NR₂S(O)₂—, wherein each R₁        is independently H, CF₃, or an optionally substituted lower        alkyl and two R₁ on the same carbon may join to form a carbonyl        (═O); and each R₂ is independently H, OH, OMe, CF₃, or an        optionally substituted lower alkyl and two R₂ on the same carbon        may join to form a carbonyl (═O); m is 0, 1 or 2; each n is        independently 0, 1, 2, or 3;    -   Y is —C(O)NHS(═O)₂R_(3b), —S(═O)₂NHC(O)R₄,        —C(O)NR₄C(═NR₃)N(R₄)₂, —C(O)NR₄C(═CR₃)N(R₄)₂, —CON(R₄)₂,        -L₁-(substituted or unsubstituted heteroalicyclic group),        -L₁-C(═NR₄)N(R₄)₂, -L₁-NR₄C(═NR₃)N(R₄)₂, -L₁-NR₄C(═CR₃)N(R₄)₂,        provided that when the heteroatom is directly bound to Z, the        heteroalicyclic group is substituted;        -   where L₁ is a bond, a substituted or unsubstituted alkyl,            substituted or unsubstituted alkenyl, or substituted or            unsubstituted alkynyl, a substituted or unsubstituted            heteroalicyclic group, a substituted or unsubstituted            heteroaryl, a substituted or unsubstituted cycloalkyl, a            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted heteroalkenyl, or a substituted or            unsubstituted heteroalkynyl;        -   where each substituent is (L_(s)R_(s)), wherein each L_(s)            is independently selected from a bond, —O—, —C(═O)—, —S—,            —S(═O)—, —S(═O)₂—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,            —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—, —C(O)O—,            —OC(O)—, C₁-C₆ alkyl, C₂-C₆ alkenyl, —C₁-C₆ fluoroalkyl,            heteroaryl, aryl, or heteroalicyclic group; and each R_(s)            is independently selected from H, halogen, —N(R₄)₂, —CN,            —NO₂, N₃, —S(═O)₂NH₂, lower alkyl, lower cycloalkyl, —C₁-C₆            fluoroalkyl, heteroaryl, or heteroalkyl; where j is 0, 1, 2,            3, or 4;        -   each R₃ is independently selected from H, —S(═O)₂R₈,            —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;        -   each R_(3b) is independently selected from substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl;        -   each R₄ is independently selected from H, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl; or two R₄ groups can            together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;            or R_(3b) and R₄ can together form a 5-, 6-, 7-, or            8-membered heterocyclic ring;    -   R₆ is H, L₂-(substituted or unsubstituted alkyl),        L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or        unsubstituted alkenyl), L₂-(substituted or unsubstituted        cycloalkenyl), L₂-(substituted or unsubstituted heteroalicyclic        group), L₂-(substituted or unsubstituted heteroaryl), or        L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O,        S, —S(═O), —S(═O)₂, C(O), —CH(OH), -(substituted or        unsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted        C₂-C₆ alkenyl);    -   R₇ is L₃-X-L₄-G₁, wherein,        -   L₃ is a bond, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            heteroalicyclic group;        -   X is a bond, O, —C(═O), —CR₉(OR₉), S, —S(═O), —S(═O)₂, —NR₉,            —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NR₉—,            —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl,            aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—,            —OC(—NR₁₀)—, or —C(═NR₁₀)O—;        -   L₄ is a bond, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl;        -   G₁ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉,            —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂,            —N(R)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R₉)₂,            —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂,            —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈,            —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted            alkyl), -L₅-(substituted or unsubstituted alkenyl),            -L₅-(substituted or unsubstituted heteroaryl), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is            —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);        -   or G₁ is W-G₅, where W is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroalicyclic group or            substituted or unsubstituted heteroaryl and G₅ is H,            tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃,            —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,            —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,            —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉,            —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(—C)₂R₈;        -   each R₈ is independently selected from substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl;        -   each R₉ is independently selected from H, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl; or two R₉ groups can            together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;            or R₈ and R₉ can together form a 5-, 6-, 7-, or 8-membered            heterocyclic ring and        -   each R₁₀ is independently selected from H, —S(═O)₂R₈,            —S(—O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;    -   R₅ is H, halogen, —N₃, —CN, —ONO₂, -L₆-(substituted or        unsubstituted C₁-C₆ alkyl), -L₆-(substituted or unsubstituted        C₂-C₆ alkenyl), -L₆-(substituted or unsubstituted heteroaryl),        or -L₆-(substituted or unsubstituted aryl), wherein L₆ is a        bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O, —OC(O)NH,        —NHC(O), —NHC(O)NH—, or —C(O)NH;    -   R₁₁ is L₇-L₁₀-G₆; wherein L₇ is a bond, —O, —S, —S(═O), —S(═O)₂,        —NH, —C(O), —C(O)NH, —NHC(O), (substituted or unsubstituted        C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);        -   L₁₀ is a bond, (substituted or unsubstituted alkyl),            (substituted or unsubstituted cycloalkyl), (substituted or            unsubstituted cycloalkenyl), (substituted or unsubstituted            heteroaryl), (substituted or unsubstituted aryl), or            (substituted or unsubstituted heteroalicyclic group), and        -   G₆ is H, CN, SCN, N₃, NO₂, halogen, OR₉, —C(═O)CF₃,            —C(═O)R₉, —SR₈, —S(═O)R₈, —S(═O)₂R₈, N(R₉)₂, tetrazolyl,            —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —C(O)NHS(═O)₂R₈,            —S(═O)₂NHC(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R₉)₂,            —NR₉C(═CR₁₀)N(R₉)₂, -L₅-(substituted or unsubstituted            alkyl), -L₅-(substituted or unsubstituted alkenyl),            -L₅-(substituted or unsubstituted heteroaryl), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is            —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);        -   or G₆ is W-G₇, wherein W is (substituted or unsubstituted            cycloalkyl), (substituted or unsubstituted cycloalkenyl),            (substituted or unsubstituted aryl), (substituted or            unsubstituted heteroalicyclic group) or a (substituted or            unsubstituted heteroaryl) and G₇ is H, tetrazolyl,            —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —ORS, —C(═O)CF₃,            —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,            —C(—NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,            —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉,            —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈,            -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted            or unsubstituted alkenyl), -L₅-(substituted or unsubstituted            heteroalkyl), -L₅-(substituted or unsubstituted heteroaryl),            -L₅-(substituted or unsubstituted heteroalicyclic group), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is —NH,            —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O); and    -   R₁₂ is L₈-L₉-R₁₃, wherein L₈ is a bond, (substituted or        unsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted        C₂-C₄ alkenyl); L₉ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O),        —NHC(O)O, —OC(O)NH, —NHC(O)NH—, —OC(O)O—, —NHC(O)—, —C(O)NH—,        —C(O)O—, or —OC(O)—; R₁₃, is H, (substituted or unsubstituted        C₁-C₆ alkyl), (substituted or unsubstituted C₃-C₆ cycloalkyl),        (substituted or unsubstituted aryl), (substituted or        unsubstituted heteroaryl), or (substituted or unsubstituted        heteroalicyclic group);    -   or R₇ and R₁₂ can together form a 4 to 8-membered heterocyclic        ring.

For any and all of the embodiments (such as, e.g. Formula (E), Formula(E-I), and Formula (E-II)), substituents are selected from among a listof alternatives. For example, in one embodiment, the heteroalicyclicgroup of Y is selected from quinolizines, dioxines, piperidines,morpholines, thiazines, tetrahydropyridines, piperazines, oxazinanones,dihydropyrroles, dihydroimidazoles, tetrahydrofurans, dihydrooxazoles,oxiranes, pyrrolidines, pyrazolidines, dihydrothiophenones,imidazolidinones, pyrrolidinones, dihydrofuranones, dioxolanones,thiazolidines, piperidinones, tetrahydronaphyridines,tetrahydroquinolines, tetrahydrothiophenes, and thiazepanes.

In further embodiments, the heteroalicyclic group of Y is selected fromthe group consisting of the following structures:

By way of example only, the heteroalicyclic group of Y is selected from

In a further or alternative embodiment, the “G” group (e.g. G₁, G₅, G₆,G₇) is any group that is used to tailor the physical and biologicalproperties of the molecule. Such tailoring/modifications are achievedusing groups which modulate acidity, basicity, lipophilicity, solubilityand other physical properties of the molecule. The physical andbiological properties modulated by such modifications to “G” include, byway of example only, solubility, in vivo absorption, and in vivometabolism. In addition, in vivo metabolism may include, by way ofexample only, controlling in vivo PK properties, off-target activities,potential toxicities associated with cypP450 interactions, drug-druginteractions, and the like. Further, modifications to “G” allow for thetailoring of the in vivo efficacy of the compound through the modulationof, by way of example, specific and non-specific protein binding toplasma proteins and lipids and tissue distribution in vivo.Additionally, such tailoring/modifications to “G” allow for the designof compounds selective for 5-lipoxygenase-activating protein over otherproteins.

In further or alternative embodiments, “G” is L₂₀-Q, wherein L₂₀ is anenzymatically cleavable linker and Q is a drug, or an affinity moiety.In further or alternative embodiments, the drug includes, by way ofexample only, leukotriene receptor antagonists and anti-inflammatoryagents. In further or alternative embodiments, the leukotriene receptorantagonists include, but are not limited to, CysLT1/CysLT2 dualantagonists and CysLT1 antagonists. In further or alternativeembodiments, the affinity moiety allow for site specific binding andinclude, but are not limited to, antibodies, antibody fragments, DNA,RNA, siRNA, and ligands.

Formula (E-II) is as follows:

-   -   wherein, Z is selected from N(R₁), S(O)_(m), CR₁═CR₁, —C≡C—,        C(R₁)₂[C(R₂)₂]_(n). [C(R₂)₂]_(n)C(R₁)₂O, OC(R₁)₂[C(R₂)₂]_(n),        [C(R₂)₂]_(n)C(R₁)₂S(O)_(m), S(O)_(m)C(R₁)₂[C(R₂)₂]_(n),        [C(R₂)₂]_(n)C(R₁)₂NR₁, NR₁C(R₁)₂[C(R₂)₂]_(n),        [C(R₂)₂]_(n)O[C(R₁)₂]_(n), [C(R₁)₂]O[C(R₂)₂]_(n), —C(O)NR₂—,        —NR₂C(O)—, —NR₂C(O)O—, —OC(O)NR₂—, —S(O)₂NR₂—, —CR₁═N—N—,        NR₂C(O)NR₂—, —OC(O)O—, S(O)₂NR₂, or —NR₂S(O)₂—, wherein each R₁        is independently H, CF₃, or an optionally substituted lower        alkyl and two R₁ on the same carbon may join to form a carbonyl        (═O); and each R₂ is independently H, OH, OMe, CF₃, or an        optionally substituted lower alkyl and two R₂ on the same carbon        may join to form a carbonyl (═O);    -   m is 0, 1 or 2; each n is independently 0, 1, 2, or 3;    -   Y is —C(O)NHS(═O)₂R_(3b), —S(═O)₂NHC(O)R₄, —C(O)NC(═NR₃)N(R₄)₂,        —C(O)NC(═CR₃)N(R₄)₂, —CON(R₄)₂, -L₁-(substituted or        unsubstituted heteroalicyclic group), -L₁-C(═NR₄)N(R₄)₂,        -L₁-NR₄C(═NR₃)N(R₄)₂, -L₁-NR₄C(═CR₃)N(R₄)₂, provided that when        the heteroatom is directly bound to Z, the heteroalicyclic group        is substituted;    -   where L₁ is a bond, a substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, or substituted or        unsubstituted alkynyl, a substituted or unsubstituted        heteroalicyclic group, a substituted or unsubstituted        heteroaryl, a substituted or unsubstituted cycloalkyl, a        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heteroalkenyl, or a substituted or unsubstituted        heteroalkynyl;    -   where each substituent is (L_(s)R_(s))_(j), wherein each L_(s)        is independently selected from a bond, —O—, —C(═O)—, —S—,        —S(═O)—, —S(═O)₂—, —N—HC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,        —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—, —C(O)O—, —OC(O)—,        C₁-C₆ alkyl, C₂-C₆ alkenyl, —C₁-C₆ fluoroalkyl, heteroaryl,        aryl, or heteroalicyclic group; and each R_(s) is independently        selected from H, halogen, —N(R₄)₂, —CN, —NO₂, N₃, —S(═O)₂NH₂,        lower alkyl, lower cycloalkyl, —C₁-C₆ fluoroalkyl, heteroaryl,        or heteroalkyl; where j is 0, 1, 2, 3, or 4;    -   each R₃ is independently selected from H, —S(═O)₂R₈,        —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl; each        R_(3b) is independently selected from substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        cycloalkyl, phenyl or benzyl; each R₄ is independently selected        from H, substituted or unsubstituted lower alkyl, substituted or        unsubstituted lower cycloalkyl, phenyl or benzyl; or two R₄        groups can together form a 5-, 6-, 7-, or 8-membered        heterocyclic ring, or R_(3b) and R₄ can together form a 5-, 6-,        7-, or 8-membered heterocyclic ring;    -   R₆ is H, L₂-(substituted or unsubstituted alkyl),        L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or        unsubstituted alkenyl), L₂-(substituted or unsubstituted        cycloalkenyl), L₂-(substituted or unsubstituted heteroalicyclic        group), L₂-(substituted or unsubstituted heteroaryl), or        L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O,        S, —S(═O), —S(═O)₂, C(O), —CH(OH), -(substituted or        unsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted        C₂-C₆ alkenyl);    -   R₇ is L₃-X-L₄-G₁, wherein, L₃ is a bond, substituted or        unsubstituted alkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted heteroalicyclic group; X is a bond, O, —C(═O),        —CR₉(OR₉), S, —S(═O), —S(═O)₂, —NR₉, —NR₉C(O), —C(O)NR₉,        —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—,        —ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,        —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₄ is        a bond, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,        substituted or unsubstituted alkynyl; G₁ is H, tetrazolyl,        —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉, —C(═O)CF₃, —C(O)NHS(═O)₂R₈,        —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R)C(O)R₉, —C(═NR₁₀)N(R₉)₂,        —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂,        —C(O)NR₉C(—CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈,        —S(—O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted alkyl),        -L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted or        unsubstituted heteroaryl), or -L₅-(substituted or unsubstituted        aryl), wherein L₅ is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—,        —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or G₁ is W-G₅, where W is a        substituted or unsubstituted aryl, substituted or unsubstituted        heteroalicyclic group or substituted or unsubstituted heteroaryl        and G₅ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈,        —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂,        —N(R₉)C(O)R₉, —C(—NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,        —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂,        —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈,        —S(—O)R₈, or —S(═O)₂R₈; each R₈ is independently selected from        substituted or unsubstituted lower alkyl, substituted or        unsubstituted lower cycloalkyl, phenyl or benzyl; each R₉ is        independently selected from H, substituted or unsubstituted        lower alkyl, substituted or unsubstituted lower cycloalkyl,        phenyl or benzyl; or two R₉ groups can together form a 5-, 6-,        7-, or 8-membered heterocyclic ring; or R₈ and R₉ can together        form a 5-, 6-, 7-, or 8-membered heterocyclic ring and each R₁₀        is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂—C(O)R₈,        —CN, —NO₂, heteroaryl, or heteroalkyl;    -   R₅ is H, halogen, —N3, —CN, —ONO₂, -L₆-(substituted or        unsubstituted C₁-C₆ alkyl), -L₆-(substituted or unsubstituted        C₂-C₆ alkenyl), -L₆-(substituted or unsubstituted heteroaryl),        or -L₆-(substituted or unsubstituted aryl), wherein L₆ is a        bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O, —OC(O)NH,        —NHC(O), —NHC(O)NH—, or —C(O)NH;    -   R₁₁ is L₇-L₁₀-G₆; wherein L₇ is a bond, —O, —S, —S(═O), —S(═O)₂,        —NH, —C(O), —C(O)NH, —NHC(O), (substituted or unsubstituted        C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);        L₁₀ is a bond, (substituted or unsubstituted alkyl),        (substituted or unsubstituted cycloalkyl), (substituted or        unsubstituted cycloalkenyl), (substituted or unsubstituted        heteroaryl), (substituted or unsubstituted aryl), or        (substituted or unsubstituted heteroalicyclic group), and G₆ is        H, CN, SCN, N₃, NO₂, halogen, OR₉, —C(═O)CF₃, —C(═O)R₉, —SR₈,        —S(═O)R₈, —S(═O)₂R₈, N(R₉)₂, tetrazolyl, —NHS(—O)₂R₈,        —S(═O)₂N(R₉)₂, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉,        —C(═NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R %)₂, —NR₉C(—CR₁₀)N(R₉)₂,        -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted or        unsubstituted alkenyl), -L₅-(substituted or unsubstituted        heteroaryl), or -L₅-(substituted or unsubstituted aryl), wherein        L₅ is —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O),        —C(O)NH, —C(O)O, or —OC(O); or G₆ is W-G₇, wherein W is        (substituted or unsubstituted cycloalkyl), (substituted or        unsubstituted cycloalkenyl), (substituted or unsubstituted        aryl), (substituted or unsubstituted heteroalicyclic group) or a        (substituted or unsubstituted heteroaryl) and G₇ is H,        tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃,        —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,        —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,        —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉,        —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈, -L₅-(substituted or        unsubstituted alkyl), -L₅-(substituted or unsubstituted        alkenyl), -L₅-(substituted or unsubstituted heteroalkyl),        -L₅-(substituted or unsubstituted heteroaryl), -L₅-(substituted        or unsubstituted heteroalicyclic group), or -L₅-(substituted or        unsubstituted aryl), wherein L₅ is —NH, —NHC(O)O, —NHC(O)NH—,        —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O);    -   R₁₂ is L₈-L₉-R₁₃, wherein L₈ is a bond, (substituted or        unsubstituted C₁-C₅ alkyl), or (substituted or unsubstituted        C₂-C₄ alkenyl); L₉ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O),        —NHC(O)O, —OC(O)NH, —NHC(O)NH—, —OC(O)O—, —NHC(O)—, —C(O)NH—,        —C(O)O—, or —OC(O)—; R₁₃, is H, (substituted or unsubstituted        C₁-C₆ alkyl), (substituted or unsubstituted C₃-C₆ cycloalkyl),        (substituted or unsubstituted aryl), (substituted or        unsubstituted heteroaryl), or (substituted or unsubstituted        heteroalicyclic group); or R₇ and R₁₂ can together form a 4 to        8-membered heterocyclic ring.

For any and all of the embodiments (such as, e.g. Formula (E), Formula(E-I), and Formula (E-II)), substituents can be selected from among froma subset of the listed alternatives. For example, in some embodiments, Zis [C(R₂)₂]_(n)C(R₁)₂O. In further or alternative embodiments, Y is-L₁-(substituted or unsubstituted heteroalicyclic group).

In further or alternative embodiments, R₆ is L₂-(substituted orunsubstituted alkyl), or L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(O)₂, —C(O), —CH(OH), or substituted or unsubstituted alkyl.

In further or alternative embodiments, R₇ is L₃-X-L₄-G; wherein, L₃ is asubstituted or unsubstituted alkyl; X is a bond, O, —C(═O), —CR₉(OR₉),S, —S(═O), —S(═O)₂, —NR₉, —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂,—OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl,aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(—NR₁₀)—, or—C(═NR₁₀)O—; and L₄ is a bond, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl. In further or alternativeembodiments, G₁ is tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,—C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,—C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉,—CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, or G₁ is W-G₅, where W is asubstituted or unsubstituted heteroalicyclic group or substituted orunsubstituted heteroaryl and G₅ is tetrazolyl, —NHS(═O)₂R₈,S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN,N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,—NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(—NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂,—CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈. In further oralternative embodiments, X is a bond, —O—, —CR₉(OR₉), S, —S(O), —S(O)₂,—NR₈, —O—N═CH, —CH═N—O, —NHC(═O) or —C(—O)NH.

In further or alternative embodiments, R₁₁ is L₇-L₁₀-G₆, wherein L₇ is abond, (substituted or unsubstituted C₁-C₆ alkyl), and L₁₀ is a(substituted or unsubstituted aryl), (substituted or unsubstitutedheteroaryl), or (substituted or unsubstituted heteroalicyclic group). Infurther or alternative embodiments, G₆ is tetrazolyl, —NHS(═O)₂R₈,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,—NR₉C(═CR₁₀)N(R₉)₂, -L₅-(substituted or unsubstituted alkyl),-L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted orunsubstituted aryl), L₅ is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—,—NHC(O), —C(O)NH, —C(O)O, or —OC(O). In further or alternativeembodiments, L₁₀ is a (substituted or unsubstituted aryl). In further oralternative embodiments, wherein G₆ is W-G₇, wherein W is (substitutedor unsubstituted heteroalicyclic group) or (substituted or unsubstitutedheteroaryl) and G₇ is tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(—NR₁₀)N(R₉)₂,—C(O)NR₉C(═CR₁₀)N(R₉)₂, —CON(R₉)₂, -L₅-(substituted or unsubstitutedalkyl), -L₅-(substituted or unsubstituted heteroaryl), -L₅-(substitutedor unsubstituted heteroalicyclic group), or -L₅-(substituted orunsubstituted aryl), L₅ is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—,—NHC(O), —C(O)NH, —C(O)O, or —OC(O).

In further or alternative embodiments, L₈ is a bond, (substituted orunsubstituted C₁-C₆ alkyl); L₉ is a bond, —O—, —S—, —S(═O), —S(═O)₂,—NH—, —C(O)—, —(CH₂)—, —NHC(O)O—, —NHC(O)—, or —C(O)NH; R₁₃ is H,(substituted or unsubstituted C₁-C₆ alkyl), or (substituted orunsubstituted C₃-C₆ cycloalkyl).

In further or alternative embodiments, the heteroalicyclic group ofgroup Y can be selected from a quinolizine, a dioxine, a piperidine, amorpholine, a thiazine, a tetrahydropyridine, a piperazine, aoxazinanone, a dihydropyrrole, a dihydroimidazole, a tetrahydrofuran, adihydrooxazole, an oxirane, a pyrrolidine, a pyrazolidine, adihydrothiophenone, an imidazolidinone, a pyrrolidinone, adihydrofuranone, a dioxolanone, a thiazolidine, a piperidinone, atetrahydronaphyridine, a tetrahydroquinoline, a tetrahydrothiophene, anda thiazepane. In further or alternative embodiments, the heteroalicyclicgroup of group Y can be selected from the group consisting of:

In further or alternative embodiments, “G” (e.g. G., G₅, G₆, G₇) isL₂₀-Q, wherein L₂₀ is an enzymatically cleavable linker and Q is a drug,or an affinity moiety. In further or alternative embodiments, the drugincludes, by way of example only, leukotriene receptor antagonists andanti-inflammatory agents. In further or alternative embodiments, theleukotriene receptor antagonists include, but are not limited to,CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further oralternative embodiments, the affinity moiety allows for site specificbinding and include, but are not limited to, antibodies, antibodyfragments, DNA, RNA, siRNA, and ligands.

In a further or alternative embodiment, the “G” group (e.g. G₁, Gs, G₆,G₇) of any of Formula (E), Formula (E-I), or Formula (E-II), is anygroup that is used to tailor the physical and biological properties ofthe molecule. Such tailoring/modifications are achieved using groupswhich modulate acidity, basicity, lipophilicity, solubility and otherphysical properties of the molecule. The physical and biologicalproperties modulated by such modifications to “G” include, by way ofexample only, solubility, in vivo absorption, and in vivo metabolism. Inaddition, in vivo metabolism may include, by way of example only,controlling in vivo PK properties, off-target activities, potentialtoxicities associated with cypP450 interactions, drug-drug interactions,and the like. Further, modifications to “G” allow for the tailoring ofthe in vivo efficacy of the compound through the modulation of, by wayof example, specific and non-specific protein binding to plasma proteinsand lipids and tissue distribution in vivo. Additionally, suchtailoring/modifications to “G” allow for the design of compoundsselective for 5-lipoxygenase-activating protein over other proteins. Infurther or alternative embodiments, “G” is L₂₀-Q, wherein L₂₀ is anenzymatically cleavable linker and Q is a drug, or an affinity moiety.In further or alternative embodiments, the drug includes, by way ofexample only, leukotriene receptor antagonists and anti-inflammatoryagents. In further or alternative embodiments, the leukotriene receptorantagonists include, but are not limited to, CysLT1/CysLT2 dualantagonists and CysLT1 antagonists. In further or alternativeembodiments, the affinity moiety allows for site specific binding andinclude, but are not limited to, antibodies, antibody fragments, DNA,RNA, siRNA, and ligands.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Formula (E) is as follows:

wherein,

-   -   Z is OC(R₁)₂[C(R₂)₂]_(n), [C(R₂)₂]_(n), or [C(R₂)₂]_(n)C(R₁)₂O        wherein each R₁ is independently H, CF₃, or an optionally        substituted lower alkyl and two R₁ on the same carbon may join        to form a carbonyl (═O); and each R₂ is independently H, OH,        OMe, CF₃, or an optionally substituted lower alkyl and two R₂ on        the same carbon may join to form a carbonyl (═O); each n is        independently 0, 1, 2, or 3;    -   Y is -L₁-(substituted or unsubstituted heteroalicyclic group),        provided that when the heteroatom is directly bound to Z, the        heteroalicyclic group is substituted;        -   where L₁ is a bond, a substituted or unsubstituted alkyl,            substituted or unsubstituted alkenyl, or substituted or            unsubstituted alkynyl, a substituted or unsubstituted            heterocycle, a substituted or unsubstituted cycloalkyl, a            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted heteroalkenyl, or a substituted or            unsubstituted heteroalkynyl;        -   where each substituent is (L_(s)R_(s))_(j), wherein each            L_(s) is independently selected from a bond, —O—, —C(═O)—,            —S—, —S(═O)—, —S(═O)₂—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—,            —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—,            —C(O)O—, —OC(O)—, C₁-C₆ alkyl, C₂-C₆ alkenyl, —C₁-C₆            fluoroalkyl, heteroaryl, aryl, or heteroalicyclic group; and            each R_(s) is independently selected from H, halogen,            —N(R₄)₂, —CN, —NO₂, N₃, —S(═O)₂NH₂, lower alkyl, lower            cycloalkyl, —C₁-C₆ fluoroalkyl, heteroaryl, or heteroalkyl;            where j is 0, 1, 2, 3, or 4;        -   each R₄ is independently selected from H, substituted or            unsubstituted lower allyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl; or two R groups can            together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;    -   R₆ is H, L₂-(substituted or unsubstituted alkyl),        L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or        unsubstituted alkenyl), L₂-(substituted or unsubstituted        cycloalkenyl), L₂-(substituted or unsubstituted heteroalicyclic        group), L₂-(substituted or unsubstituted heteroaryl), or        L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O,        S, —S(═O), —S(═O)₂, C(O), —CH(OH), -(substituted or        unsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted        C₂-C₆ alkenyl);    -   R₇ is L₃-X-L₄-G₁, wherein,        -   L₃ is a bond, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            heteroalicyclic group;        -   X is a bond, O, —C(═O), —CR₉(OR₉), S, —S(═O), —S(═O)₂, —NR₉,            —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NR₉—,            —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl,            aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(—NR₁₀)NR₉—,            —OC(═NR₁₀)—, or —C(═NR₁₀)O—;        -   L₄ is a bond, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkenyl, substituted or unsubstituted alkynyl;        -   G₁ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉,            —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂,            —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,            —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(—NR₁₀)N(R)₂,            —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈,            —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted            alkyl), -L₅-(substituted or unsubstituted alkenyl),            -L₅-(substituted or unsubstituted heteroaryl), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is            —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);        -   or G₁ is W-G₅, where W is a substituted or unsubstituted            aryl, substituted or unsubstituted heteroalicyclic group or            substituted or unsubstituted heteroaryl and G₅ is H,            tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃,            —C(O)NHS(—O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,            C(—NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,            —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉,            —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(—O)₂R₈;        -   each R₈ is independently selected from substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl;        -   each R₉ is independently selected from H, substituted or            unsubstituted lower alkyl, substituted or unsubstituted            lower cycloalkyl, phenyl or benzyl; or two R₉ groups can            together form a 5-, 6-, 7-, or 8-membered heterocyclic ring;            or R₈ and R₉ can together form a 5-, 6-, 7-, or 8-membered            heterocyclic ring and        -   each R₁₀ is independently selected from H, —S(—O)₂R₈,            —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;    -   R₅ is H, halogen, substituted or unsubstituted C₁-C₆ alkyl,        substituted or unsubstituted O—C₁-C₆ alkyl;    -   R₁₁ is L₇-L₁₀-G₆; wherein L₇ is a bond, —O, —S, —S(—O), —S(O)₂,        —NH, —C(O), —C(O)NH, —NHC(O), (substituted or unsubstituted        C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);        -   L₁₀ is a bond, (substituted or unsubstituted alkyl),            (substituted or unsubstituted cycloalkyl), (substituted or            unsubstituted cycloalkenyl), (substituted or unsubstituted            heteroaryl), (substituted or unsubstituted aryl), or            (substituted or unsubstituted heteroalicyclic group), and        -   G₆ is H, CN, SCN, N₃, NO₂, halogen, OR₉, —C(═O)CF₃,            —C(═O)R₉, —SR₉, —S(═O)R₈, —S(═O)₂R₈, N(R₉)₂, tetrazolyl,            —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —C(O)NHS(═O)₂R₈,            —S(═O)₂NHC(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,            —NR₉C(═CR₁₀)N(R₉)₂, -L₅-(substituted or unsubstituted            alkyl), -L₅-(substituted or unsubstituted alkenyl),            -L₅-(substituted or unsubstituted heteroaryl), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is            —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);        -   or G₆ is W-G₇, wherein W is (substituted or unsubstituted            cycloalkyl), (substituted or unsubstituted cycloalkenyl),            (substituted or unsubstituted aryl), (substituted or            unsubstituted heteroalicyclic group) or a (substituted or            unsubstituted heteroaryl) and G₇ is H, tetrazolyl,            —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃,            —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉,            —C(═NR₁₀)N(R₉)₂, —NR₉C(—NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,            —C(O)NR₉C(—NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉,            —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₉, or —S(═O)₂R₉,            -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted            or unsubstituted alkenyl), -L₅-(substituted or unsubstituted            heteroalkyl), -L₅-(substituted or unsubstituted heteroaryl),            -L₅-(substituted or unsubstituted heteroalicyclic group), or            -L₅-(substituted or unsubstituted aryl), wherein L₅ is —NH,            —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH,            —C(O)O, or —OC(O);    -   R₁₂ is H, (substituted or unsubstituted C₁-C₆ alkyl), or        (substituted or unsubstituted C₂-C₄ alkenyl); or an active        metabolite; or solvate, or pharmaceutically acceptable salt, or        a pharmaceutically acceptable prodrug thereof.

For any and all of the embodiments (such as, e.g. Formula (E), Formula(E-I), and Formula (E-II)), substituents can be selected from among froma subset of the listed alternatives. For example, in some embodiments, Yis -L₁-(substituted or unsubstituted heteroalicyclic group). In furtheror alternative embodiments, the heteroalicyclic group is selected fromthe group consisting of a quinolizine, a dioxine, a piperidine, amorpholine, a thiazine, a tekrahydropyridine, a piperazine, aoxazinanone, a dihydropyrrole, a dihydroimidazole, a tetrahydrofuran, adihydrooxazole, an oxirane, a pyrrolidine, a pyrazolidine, adihydrothiophenone, an imidazolidinone, a pyrrolidinone, adihydrofuranone, a dioxolanone, a thiazolidine, a piperidinone, atetrahydronaphyridine, a tetrahydroquinoline, a tetrahydrothiophene, anindoline, a tetrahydroquinoline, and a thiazepane. In further oralternative embodiments, the heteroalicyclic group is selected from thegroup consisting of:

In further or alternative embodiments, R₆ is L₂-(substituted orunsubstituted alkyl), or L₂-(substituted or unsubstituted cycloalkyl),or L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(O)₂, —C(O), —CH(OH), or substituted or unsubstituted alkyl.

In further or alternative embodiments, R₇ is L₃-X-L₄-G₁; wherein, L₃ isa substituted or unsubstituted alkyl; X is a bond, O, —C(═O), —CR₉(OR₉),S, —S(═O), —S(═O)₂, —NR₉, —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂,—OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl,aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or—C(═NR₁₀)O—; and L₄ is a bond or a substituted or unsubstituted alkyl.

In further or alternative embodiments, G, is tetrazolyl, —NHS(═O)₂R₈,S(═O)₂N(R₉)₂, —OR₉, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN,N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,—NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂,—CO₂R₉, —C(O)R₉, —CON(P₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, or G₁ is W-G₅,where W is a substituted or unsubstituted heteroalicyclic group orsubstituted or unsubstituted heteroaryl and Gs is tetrazolyl,—NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈,—S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂,—C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or—S(═O)₂R₈.

In further or alternative embodiments, X is a bond, —O—, —CR₉(OR₉), S,—S(O), —S(O)₂, —NR₈, —O—N═CH, —CH═N—O, —NHC(═O) or —C(═O)NH.

In further or alternative embodiments, R₁₂ is H and R₁₁ is L₇-L₁₀-G₆,wherein: L₇ is a bond, (substituted or unsubstituted C₁-C₆ alkyl); andL₁₀ is a (substituted or unsubstituted aryl), (substituted orunsubstituted heteroaryl), or (substituted or unsubstitutedheteroalicyclic group). In further or alternative embodiments, L₁₀ is a(substituted or unsubstituted aryl).

In further or alternative embodiments, G₆ is W-G₇, wherein W is(substituted or unsubstituted heteroalicyclic group) or (substituted orunsubstituted heteroaryl) and G₇ is H, tetrazolyl, —NHS(═O)₂R₈,S(═O)₂N(R₉), OH, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂,—C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CON(R₉)₂,-L₅-(substituted or unsubstituted alkyl), -L₅-(substituted orunsubstituted heteroaryl), -L₅-(substituted or unsubstitutedheteroalicyclic group), or -L₅-(substituted or unsubstituted aryl), L₅is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH, —C(O)O,or —OC(O).

In some embodiments, Z is [C(R₂)₂]_(n)C(R₁)₂O.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Further embodiments of Formula (E), Formula (E-I) and Formula (E-II),include, but are not limited to, compounds shown in FIGS. 8-11 and inTables 1-3.

TABLE 1 Non-aromatic R₁ substituents and R₂ chloro/bromo substituents

Compound # R₁ R₂ R₃ R₄ M + H 1-1 (S)-N-t-Butoxyoarbonyl- Cl2-methyl-2-propylthio H 651 2-pyrrolidinemethyl 1-2 (S)-N-Acetyl-2 Cl2-methyl-2-propylthio H 593 pyrrolidinemethyl 1-3(R)-N-t-Butoxycarbonyl- Cl 2-methyl-2-propylthio H 6512-pyrrolidinemethyl 1-4 (S)-2-Pyrrolidone-5- Cl 2-methyl-2-propylthio H543 methyl 1-5 (R)-2-Pyrrolidone-5- Cl 2-methyl-2-propylthio H 543methyl 1-6 (R)-N-Acetyl 2- Cl 2-methyl-2-propylthio H 571pyrrolidinemethyl 1-7 (R)-N-Methylsulfonyl 2- Cl 2-methyl-2-propylthio H629 pyrrolidinemethyl (M + Na) 1-8 (S)-N-Methylsulfonyl 2- Cl2-methyl-2-propylthio H 607, 629 pyrrolidinemethyl (M + Na) 1-9(R)-2-pyrrolidinemethyl Cl 2-methyl-2-propylthio H see Exp. 1-10N-Trifluoroacetyl 2- Cl 2-methyl-2-propylthio H 625 pyrrolidinemethyl1-11 N-t-Butoxycarbonyl-4,5- Cl 2-methyl-2-propylthio H 628dihydroimidazol-2- ylmethyl 1-12 4,5-Dihydroimidazol-2- Cl2-methyl-2-propylthio H 528 ylmethyl 1-13 (S)-N-t-Butoxycarbonyl Cl2-methyl-2-propylthio H 699 indoline-2-methyl (M + Na) 1-142-(4-Morpholine)acetyl Cl 2-methyl-2-propylthio H 573 1-15(S)-Indoline-2-methyl Cl 2-methyl-2-propylthio H 577 1-16 (S)-N-Acetylindoline-2- Cl 2-methyl-2-propythio H 619, 641 methyl (M + Na) 1-17(S)-N-Acetyl indoline-2- Cl 2-methyl-2-propylthio H 651 methylS,S-dioxide 1-18 (S)-N- Cl 2-methyl-2-propylthio H 597Cyclopropylcarbonyl-2- pyrrolidinemethyl 1-19 (S)-N-Benzoyl-2- Cl2-methyl-2-propylthio H 633 pyrrolidinemethyl 1-20 (S)-N-(2- Cl2-methyl-2-propylthio H 599 Methylpropanoyl)-2- pyrrolidinemethyl 1-21(S)-N-Propanoyl-2- Cl 2-methyl-2-propylthio H 585 pyrrolidinemethyl 1-22N-t-Butoxycarbonyl Cl 2-methyl-2-propylthio H 699 indoline-2-methyl (M +Na) 1-23 Indoline-2-methyl Cl 2-methyl-2-propylthio H 577 1-24 N-Acetylindoline-2- Cl 2-methyl-2-propylthio H 619 methyl 1-25 (S)-N-Acetylindoline-2- Cl 2-methyl-2-propylthio-S- H 635 methyl oxide 1-26(S)-N-Acetyl indoline-2- Cl benzyl H 621 methyl 1-27 (S)-N-Acetylindoline-2- Cl H H 553 methyl (M + Na) 1-28 (S)-N-Acetyl-2- Cl H H seeExp. pyrrolidinemethyl 1-29 (S)-N-Acetyl-2- Cl 3,3-dimethylbutanoyl H581 pyrrolidinemethyl 1-30 (S)-N-Acetyl indoline-2- Cl3,3-dimethylbutanoyl H 629 methyl 1-31 (S)-N-Acetyl indoline-2- Cl ethylH 599 methyl 1-32 (S)-N-Acetyl indoline-2- Cl propyl H 573 methyl 1-33(S)-N-Acetyl indoline-2- Cl 2-methylpropanoyl H 601 methyl 1-34(S)-N-Acetyl indoline-2- Cl cyclopropylcarbonyl H 599 methyl 1-35(S)-N-Acetyl indoline-2- Cl benzoyl H 635 methyl 1-36 (S)-N-Acetylindoline-2- Cl cyclobutylcarbonyl H 613 methyl 1-37 (S)-N-Acetylindoline-2- Cl acetyl H 573 methyl 1-38 (S)-N-Acetyl indoline-2- Clpropanoyl H 587 methyl 1-39 (S)-N-Acetyl indoline-2- Cl 2-methylpropyl H609 methyl (M + Na) 1-40 (S)-N-Acetyl indoline-2- Cl3,3-dimethylbut-1-yl H 615 methyl 1-41 (S)-N-Acetyl indoline-2- Clcyclobutylmethyl H 621 methyl (M + Na) 1-42 (S)-N-(4-Phenylbenzoyl)- Cl2-methyl-2-propylthio H 709 2-pyrrolidinemethyl 1-43(S)-N-(Phenylacetyl)-2- Cl 2-methyl-2-propylthio H 647 pyrrolidinemethyl1-44 (S)-N-(3- Cl 2-methyl-2-propylthio H 661 Phenylpropanoyl)-2-pyrrolidinemethyl 1-45 (S)-N-(3- Cl 2-methyl-2-propylthio H 725Phenoxybenzoyl)-2- pyrrolidinemethyl 1-46 (S)-N-(4- Cl2-methyl-2-propylthio H 725 Phenoxybenzoyl)-2- pyrrolidinemethyl 1-47(S)-N-(Nicotinoyl)-2- Cl 2-methyl-2-propylthio H 634 pyrrolidinemethyl1-48 (S)-N-(Pyridin-4- Cl 2-methyl-2-propylthio H 634 ylcarbonyl)-2-pyrrolidinemethyl 1-49 (S)-N-(4-Phenylbenzoyl)- Cl 2-methyl-2-propylthioEt 637 2-pyrrolidinemethyl 1-50 (S)-N-(Phenylacetyl)-2- Cl2-methyl-2-propylthio Et 675 pyrrolidinemethyl 1-51 (S)-N-(3- Cl2-methyl-2-propylthio Et 689 Phenylpropanoyl)-2- pyrrolidinemethyl 1-52(S)-N- Cl 2-methyl-2-propylthio Et 701 (Phenylcyclopropylcarbonyl)-2-pyrrolidinemethyl 1-53 (S)-N-(Nicotinoyl)-2- Cl2-methyl-2-propylthio Et 662 pyrrolidinemethyl 1-54 (S)-N-(Pyridin-4- Cl2-methyl-2-propylthio Et 662 ylcarbonyl)-2- pyrrolidinemethyl 1-55(S)-N- Cl 2-methyl-2-propylthio H 673 (Phenylcyclopropylcarbonyl)-2-pyrrolidinemethyl 1-56 (S)-N-(4-Bhlorobenzoyl)- Cl2-methyl-2-propylthio H 667 2-pyrrolidinemethyl 1-57 (S)-N-(4-2-methyl-2-propylthio H 754 Benzyloxyphenylacetyl)- Cl2-pyrrolidinemethyl 1-58 (S)-N-(4- Cl 2-methyl-2-propylthio Et 781Benzyloxyphenylacetyl)- 2-pyrrolidinemethyl 1-59 N-(tert Cl2-methyl-2-propylthio H 644 Butoxycarbonyl)- piperidin-2-ylmethyl 1-60N-(tert Cl 2-methyl-2-propylthio Et 572 Butoxycarbonyl)piperidin- (M −BOC) 2-ylmethyl 1-61 (S)-N-(2- Cl 2-methyl-2-propylthio Et 801Bromoethoxycarbonyl) indoline-2-methyl 1-62 (S)-Pyrrolidin-2-ylmethyl Cl2-methyl-2-propylthio H 529 1-63 2-(2-Methyl-1,3-dioxolan- Br2-methyl-2-propylthio H 604 2-yl)ethyl

TABLE 2 R₂ Aryl substituents

Compound # R₁ R₂ R₃ M + H 2-1 (S)-N-t- 2-thiazolyl 2-methyl-2-propylthio700 Butoxycarbonyl-2- (M + Na) pyrrolidinemethyl 2-2 (S)-2- 2-thiazolyl2-methyl-2-propylthio 579 Pyrrolidinemethyl 2-3 (S)-N-Acetyl-2-2-thiazolyl 2-methyl -2-propylthio 620 pyrrolidinemethyl 2-4(S)-N-Acetyl-2- 2-thiazolyl H 532 pyrrolidinemethyl 2-5 (S)-N-Acetyl-2-2-methoxy-4- 2-methyl-2-propylthio 694 indolinemethyl pyridazinyl 2-6(S)-N-Acetyl-2- 2-methoxy-4- 2-methyl-2-propylthio 645 pyrrolidinemethylpyridazinyl 2-7 (S)-N-Acetyl-2- 2-methoxypyridin- 2-methyl-2-propylthio692 indolinemethyl 5-yl 2-8 (S)-N-Acetyl-2- 2-methoxythiazol-2-methyl-2-propylthio 698 indolinemethyl 4-yl 2-9 (S)-N-Acetyl-2-5-methoxypyridin- 2-methyl-2-propylthio 692 indolinemethyl 2-yl 2-102-(2-Methyl-1,3- 2-methoxypyridin- 2-methyl-2-propylthio 633dioxolan-2-yl)ethyl 5-yl 2-11 N-(Methoxyacetyl) 5- 2-methyl-2-propylthio760 indolin-2-ylmethyl trifluoromethylpyri din-2-yl

TABLE 3 Non-heteroaryl indole tertiary alcohols

Compound # R₁ R₂ R₄ M + H 3-1 2-(4-Morpholine)acetyl 4-chlorobenzyl2-hydroxy-2- 545 methyprop-1-yl 3-2 N-t-butoxycarbonyl-2- 4-chlorobenzyl 2-hydroxy-2- 543 pyrrolidinemethyl methyprop-1-yl (M − BOC, +Na + H₂O) 3-3 N-t-butoxycarbonyl-2- pyridin-2- 2-hydroxy-2- 510pyrrolidinemethyl ylmethyl methyprop-1-yl (M − BOC, + Na + H₂O) 3-4N-acetyl-2-pyrrolidinemethyl 4-chlorobenzyl 2-hydroxy-2- 543methylprop-1-yl 3-5 N-acetyl-2-pyrrolidinemethyl pyridin-2- 2-hydroxy-2-511 ylmethyl methyprop-1-yl 3-6 (S)-N-t-butoxycarbonyl-2- 4-chlorobenzyl1-hydroxy-2,2- 637 pyrrolidinemethyl dimethyprop-3-yl (M + Na)

In one aspect, provided herein is a compound selected from among:

-   (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 1-1);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-2);    (R)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 1-3);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-5-oxo-pyrrolidin-2-ylmethoxy)-1H-indo-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-4);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-5-oxo-pyrrolidin-2-p    ylmethoxy), 1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound    1-5);    3-[5-((R)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-6);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-7);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-8);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-9);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(2,2,2-trifluoro-acetyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-10);    2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-4,5-dihydro-imidazole-1-carboxylic    acid tert-butyl ester (Compound 1-11);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-12);    (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester (Compound 1-13);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2-morpholin-4-yl-2-oxo-ethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-14);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[(S)-1-(2,3-dihydro-1H-indol-2-yl)methoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-15);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-16);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(2-methyl-propane-2-sulfonyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-17);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-cyclopropanecarbonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-18);    3-[5-((S)-1-benzoyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-19);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-isobutyryl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-20);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-propionyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (compound 1-21);    2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester (Compound 1-22);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2,3-dihydro-1H-indol-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-23);    3-[5-(1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-24);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(2-methyl-propane-2-sulfinyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-25);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-benzyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-26);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-27);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-28);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyryl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-29);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyryl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-30);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-ethyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-31);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-propyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-32);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-isobutyryl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-33);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclopropanecarbonyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-34);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-benzoyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-35);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclobutanecarbonyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-36);    3-[3-acetyl-5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-37);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-propionyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-38);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-isobutyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-39);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-40);    3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclobutylmethyl-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-41);    3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-ylmethoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-42);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(1-phenylacetyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-43);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenyl-propionyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-44);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenoxy-benzoyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-45);    3-f{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(4-phenoxy-benzoyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-46);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-47);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-48);    3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-ylmethoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-49);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(1-phenylacetyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-50);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenyl-propionyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-51);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-((S)-2-phenyl-cyclopropanecarbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-52);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-53);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-54);    3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-((R)-2-phenyl-cyclopropanecarbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-55);    3-[3-tert-butylsulfanyl-5-[(S)-1-(4-chloro-benzoyl)-pyrrolidin-2-ylmethoxy]-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-56);    3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-ylmethoxy}-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-57);    3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-ylmethoxy}-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid ethyl ester (Compound 1-58);    2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-piperidine-1-carboxylic    acid tert-butyl ester (Compound 1-59);    2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-ethoxycarbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-piperidine-1-carboxylic    acid tert-butyl ester (Compound 1-60);    2-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-2-(2-ethoxy-carbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-2,3-hydro-indole-1-carboxylic    acid 2-bromo-ethyl ester (Compound 1-61);    3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 1-62);    3-{1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 1-63);    (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-thiazol-2-yl-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 2-1);    3-[3-tert-butylsulfanyl-5-((S)-1-pyrrolidin-2-ylmethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 2-2);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 2-3);    3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic    acid (Compound 2-4);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-5);    3-{5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-6);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-7);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(2-methoxy-thiazol-4-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-8);    3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-9);    3-{3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-10);    3-{3-tert-butylsulfanyl-5-[(S)-1-(2-methoxy-acetyl)-2,3-dihydro-1H-indol-2-ylmethoxy]-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic    acid (Compound 2-11);    2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-morpholin-4-yl-ethanone    (Compound 3-1);    (R)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 3-2);    (R)-2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-[1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 3-3);    1-{(R)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yl}-ethanone    (Compound 3-4);    1-{(R)-2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl]-pyrrolidin-1-yl}-ethanone    (Compound 3-5); and    (S)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(3-hydroxy-2,2-dimethyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic    acid tert-butyl ester (Compound 3-6).

Synthesis of Compounds

Compounds described in the prior section may be synthesized usingstandard synthetic techniques known to those of skill in the art orusing methods known in the art in combination with methods describedherein. In additions, solvents, temperatures and other reactionconditions presented herein may vary according to those of skill in theart.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.), orSigma Chemical Co. (St. Louis, Mo.). The compounds described herein, andother related compounds having different substituents can be synthesizedusing techniques and materials known to those of skill in the art, suchas described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4^(th)Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th)Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVEGROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999) (all of which areincorporated by reference in their entirety). General methods for thepreparation of compound as disclosed herein may be derived from knownreactions in the field, and the reactions may be modified by the use ofappropriate reagents and conditions, as would be recognized by theskilled person, for the introduction of the various moieties found inthe formulae as provided herein. As a guide the following syntheticmethods may be utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. Table 4 entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups.

TABLE 4 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Protecting groups are used toblock some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. Protective groups can be removed by acid, base, andhydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, or they may be blocked with oxidatively-removable protectivegroups such as 2,4-dimethoxybenzyl, while co-existing amino groups maybe blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd₀-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate-amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference in their entirety.

Indole containing compounds can be prepared using standard literatureprocedures such as those found in Katritzky, “Handbook of HeterocyclicChemistry” Pergamon Press, Oxford, 1986; Pindur et al, J. HeterocyclicChem., vol 25, 1, 1987, and Robinson “The Fisher Indole Synthesis”, JohnWiley & Sons, Chichester, New York, 1982, each of which is hereinincorporated by reference in their entirety.

A non-limiting example of the synthetic approach toward indole compoundsdescribed herein is shown according to reaction Scheme I shown in FIG.1, wherein a 4-substituted anilines (I-1) can be converted to thecorresponding hydrazine (I-2) using standard methodology. Reaction ofhydrazine (I-2) with an appropriately substituted ketone (I-3) understandard Fisher-indolization conditions yields the indole (I-4). Indole(I-6) results from the N-alkylation of (I-4) with a benzyl halide (I-5)(or tosylate (OTs) or mesylate (OMs)) in a solvent such astetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of abase such as NaH. In the case where the 5-substituent on the indole ringis methoxy (i.e. Z is MeO) the methyl group can be removed understandard conditions, for example using BBr₃, in a solvent such as CH₂Cl₂to afford the phenol (I-7). This phenol can be alkylated using anelectrophile (YX) to provide the alkylated product (I-8). Alternatively,in the case when the 5-substituent on the indole ring is, for example, ahalide or triflate (OTf, I-7) it can be coupled with a wide variety ofreagents using standard metal mediated coupling reactions well known tothose skilled in the art of organic synthesis to afford alternatecompounds of structure (I-6). Such chemistry is described inComprehensive Organometallic Chemistry II, vol 12, Pergamon, edited byAbel, Stone and Wilkinson. The Z substitutent of the indole (I-6) can befurther modified using standard chemical procedures. In addition, whenR₇ or R₆ is a bromo or iodine, standard cross coupling reactions allowthe introduction of a variety of functional groups using procedures wellknown to those practiced in the art of organic synthesis. Furthermore,when R₇ is H, it is possible, under certain conditions, toregioselectively lithiate using a strong base such as nBuLi and thencondense the anion with an electrophile to introduce substituents at C-2(see Hasan et al, J. Org. Chem., 46, 157-164, 1981).

Another non-limiting example of the synthetic approach toward compoundsdescribed herein is shown according to reaction Scheme II in FIG. 2.Commencing with the hydrazine 1-2, N-alkylation with a benzyl halide (ortosylate or mesylate; I-5) using the conditions described above,provides the hydrazine derivative (II-1). Reaction with an appropriatelysubstituted ketone (I-3) using standard Fisher idolization conditionsprovides the indole (I-6).

Another non-limiting example of the synthetic approach toward compoundsdescribed herein is shown according to reaction Scheme III in FIG. 2,wherein 3-1H-indoles (III-1) can be prepared directly using theprocedures described above or, alternatively, they can be prepared from3-thioindoles by treatment with moist AlCl₃ in a solvent such as CH₂Cl₂.Functionalization at the 3-position can be achieved using a variety ofreactions and procedures to allow the introduction of a wide range ofsubstituents. By way of example only, acylation using an acid chloride(or anhydride) in the presence of a Lewis acid such as AlCl₃, allows forthe introduction of acyl groups (I-6; R₆=C(O)R′) see Murakami et al.Heterocycles, v14, 1939-1941, 1980 and references cited therein.Commencing with (III-1), and using, by way of example only, sulfenicchlorides in a suitable solvent, compounds of general structure (III-2)wherein R₆ is SR″ can be prepared (Raban, J. Org. Chem., v45, 1688,1980). Similar chemistry using indole (III-3) can be performed or,alternatively, diarlydisulfides in the presence of a base such as NaH inDMF can be used to generate (III-4) (Atkinson et al, Synthesis, 480-481,1988). The reaction of electron deficient olefins with 3-H indoles(III-1) or (III-3) in the presence of a Lewis acid (such asYb(OTf)₃.3H₂O) allows the installation of 3-alkyl substituents ofgeneral structure (III-2) or (III-4) (where R₆ is a substituted alkylgroup; see Harrington and Kerr, Synlett, 1047-1048, 1996).Alternatively, indole (III-3) can be reacted with benzyl derivatives(I-5) in warm DMF to yield (III-4) where R₆ is a substituted benzylgroup (Jacobs et al, J. Med. Chem., v36, 394-409, 1993).

Further Synthesis of Indole and Indole-Type Compounds

Additional non-limiting examples of the synthetic strategy toward indoleor indole-like scaffolds for compounds described herein includemodifications to various syntheses of indoles, including, but notlimited to; Batcho-Leimgruber Indole Synthesis, Reissert IndoleSynthesis, Hegedus Indole Synthesis, Fukuyama Indole Synthesis, SugasawaIndole Synthesis, Bischler Indole Synthesis, Gassman Indole Synthesis,Fischer Indole Synthesis, Japp-Klingemann Indole Synthesis, BuchwaldIndole Synthesis, Larock Indole Synthesis, Bartoli Indole Synthesis,Castro Indole Synthesis, Hemetsberger Indole Synthesis, Mori-Ban IndoleSynthesis, Madelung Indole Synthesis, Nenitzescu Indole Synthesis, andother unnamed reactions. Non-limiting examples of such synthetic methodsare shown in FIGS. 3-7.

Further Forms of Compounds

Compounds described herein can be prepared as a pharmaceuticallyacceptable acid addition salt (which is a type of a pharmaceuticallyacceptable salt) by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, including, butnot limited to, inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid,and the like; and organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroaceticacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid,ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

Alternatively, compounds described herein can be prepared as apharmaceutically acceptable base addition salts (which is a type of apharmaceutically acceptable salt) by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base,including, but not limited to organic bases such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like and inorganic bases such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like.

Compounds described herein can be prepared as a pharmaceuticallyacceptable salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, for example an alkali metalion, an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base. In addition, the salt forms of the disclosed compounds canbe prepared using salts of the starting materials or intermediates.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.By way of example only, hydrates of compounds described herein can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents including, but not limited to,dioxane, tetrahydrofuran or methanol. In addition, the compoundsprovided herein can exist in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

Compounds described herein may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

Compounds of Formula (E), Formula (E-I) and Formula (E-II), inunoxidized form can be prepared from N-oxides of compounds of Formula(E), Formula (E-I) and/or Formula (E-II), by treating with a reducingagent, such as, but not limited to, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorustrichloride, tribromide, or the like in a suitable inert organicsolvent, such as, but not limited to, acetonitrile, ethanol, aqueousdioxane, or the like at 0 to 80° C.

Compounds provided herein can be prepared as prodrugs. Prodrugs aregenerally drug precursors that, following administration to a subjectand subsequent absorption, are converted to an active, or a more activespecies via some process, such as conversion by a metabolic pathway.Some prodrugs have a chemical group present on the prod-rug that rendersit less active and/or confers solubility or some other property to thedrug. Once the chemical group has been cleaved and/or modified from theprodrug the active drug is generated. Prodrugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent is not. The prodrug may also have improved solubilityin pharmaceutical compositions over the parent drug.

Prodrugs may be designed as reversible drug derivatives, for use asmodifiers to enhance drug transport to site-specific tissues. The designof prodrugs to date has been to increase the effective water solubilityof the therapeutic compound for targeting to regions where water is theprincipal solvent. See, e.g., Fedorak et al., Am. J. Physiol.,269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994);Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H.Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int.J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci.,64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, all incorporated herein in theirentirety.

Additionally, prodrug derivatives of compounds provided herein can beprepared by methods known to those of ordinary skill in the art (e.g.,for further details see Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985). By way of example only,appropriate prodrugs can be prepared by reacting a non-derivatizedcompound of any of Formula (E), Formula (E-), or Formula (E-II), with asuitable carbamylating agent, such as, but not limited to,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike. Prodrug forms of the herein described compounds, wherein theprodrug is metabolized in vivo to produce a derivative as set forthherein are included within the scope of the claims. Indeed, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Sites on the aromatic ring portion of compounds described herein can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. The compounds described herein may possessone or more stereocenters and each center may exist in the R or Sconfiguration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Compounds described herein can be preparedas their individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of the compoundsdescribed herein, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chiralchromatography, or preferably, by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981, herein incorporated by reference in its entirety.

Additionally, the compounds and methods provided herein may exist asgeometric isomers. The compounds and methods provided herein include allcis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well asthe appropriate mixtures thereof. In some situations, compounds mayexist as tautomers. All tautomers are included within the formulasdescribed herein are provided by compounds and methods herein. Inadditional embodiments of the compounds and methods provided herein,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion may also be useful forthe applications described herein.

Routes of Administration

Suitable routes of administration include, but are not limited to,intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

Alternately, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto an organ, often in a depot preparation or sustained releaseformulation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Furthermore, one may administer the drug in atargeted drug delivery system, for example, in a liposome coated withorgan-specific antibody. The liposomes will be targeted to and taken upselectively by the organ. In addition, the drug may be provided in theform of a rapid release formulation, in the form of an extended releaseformulation, or in the form of an intermediate release formulation.

Pharmaceutical Composition/Formulation

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

Provided herein are pharmaceutical compositions that include a compounddescribed herein, and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In addition, the compounds described hereincan be administered as pharmaceutical compositions in which compoundsdescribed herein are mixed with other active ingredients, as incombination therapy.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds provided herein are administered in apharmaceutical composition to a mammal having a disease or condition tobe treated. Preferably, the mammal is a human. A therapeuticallyeffective amount can vary widely depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds can be used singly or incombination with one or more therapeutic agents as components ofmixtures.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

For oral administration, compounds provided herein can be formulatedreadily by combining the active compounds with pharmaceuticallyacceptable carriers or excipients well known in the art. Such carriersenable the compounds described herein to be formulated as tablets,powders, pills, dragees, capsules, liquids, gels, syrups, elixirs,slurries, suspensions and the like, for oral ingestion by a patient tobe treated.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as: for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestaffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in a conventional manner.Parental injections may involve bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form, e.g.,in ampoules or in multi-dose containers, with an added preservative. Thepharmaceutical composition of any of Formula (E), Formula (E-I), orFormula (E-II), may be in a form suitable for parenteral injection as asterile suspensions, solutions or emulsions in oily or aqueous vehicles,and may contain formulatory agents such as suspending, stabilizingand/or dispersing agents. Pharmaceutical formulations for parenteraladministration include aqueous solutions of the active compounds inwater-soluble form. Additionally, suspensions of the active compoundsmay be prepared as appropriate oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions. Alternatively, the active ingredient may be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

The compounds described herein can be administered topically and can beformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compounds can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

For administration by inhalation, the compounds described herein may bein a form as an aerosol, a mist or a powder. Pharmaceutical compositionsof any of Formula (E), Formula (E-I), or Formula (E-II), areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebuliser, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Pharmaceutical compositions may be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. Pharmaceutical compositionscomprising a compound described herein may be manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions will include at least onepharmaceutically acceptable carrier, diluent or excipient and a compounddescribed herein as an active ingredient in free-acid or free-base form,or in a pharmaceutically acceptable salt form. In addition, the methodsand pharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein. Inaddition, the pharmaceutical compositions may include other medicinal orpharmaceutical agents, carriers, adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, and/or buffers. In addition, thepharmaceutical compositions can also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The compositions may be inliquid solutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionsmay also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and so forth.

A composition comprising a compound described herein can illustrativelytake the form of a liquid where the agents are present in solution, insuspension or both. Typically when the composition is administered as asolution or suspension a first portion of the agent is present insolution and a second portion of the agent is present in particulateform, in suspension in a liquid matrix. In some embodiments, a liquidcomposition may include a gel formulation. In other embodiments, theliquid composition is aqueous.

Useful aqueous suspension can also contain one or more polymers assuspending agents. Useful polymers include water-soluble polymers suchas cellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Useful compositions can also comprise an mucoadhesive polymer,selected for example from carboxymethylcellulose, carbomer (acrylic acidpolymer), poly(methylmethacrylate), polyacrylamide, polycarbophil,acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

Useful compositions may also include solubilizing agents to aid in thesolubility of a compound described herein. The term “solubilizing agent”generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Certain acceptable nonionicsurfactants, for example polysorbate 80, can be useful as solubilizingagents, as can ophthalmically acceptable glycols, polyglycols, e.g.,polyethylene glycol 400, and glycol ethers.

Useful compositions may also include one or more pH adjusting agents orbuffering agents, including acids such as acetic, boric, citric, lactic,phosphoric and hydrochloric acids; bases such as sodium hydroxide,sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodiumlactate and tris-hydroxymethylaminomethane; and buffers such ascitrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids,bases and buffers are included in an amount required to maintain pH ofthe composition in an acceptable range.

Useful compositions may also include one or more salts in an amountrequired to bring osmolality of the composition into an acceptablerange. Such salts include those having sodium, potassium or ammoniumcations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful compositions may also include one or more preservatives toinhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Still other useful compositions may include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions may include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

Aqueous suspension compositions can be packaged in single-dosenon-reclosable containers. Alternatively, multiple-dose reclosablecontainers can be used, in which case it is typical to include apreservative in the composition.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as N-methylpyrrolidone also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

All of the formulations described herein may benefit from antioxidants,metal chelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the treatment of leukotriene-dependent or leukotrienemediated diseases or conditions. In addition, a method for treating anyof the diseases or conditions described herein in a subject in need ofsuch treatment, involves administration of pharmaceutical compositionscontaining at least one compound described herein, or a pharmaceuticallyacceptable salt, pharmaceutically acceptable N-oxide, pharmaceuticallyactive metabolite, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days,and 365 days. The dose reduction during a drug holiday may be from10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dosemay conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described herein arefrom about 0.01 to 2.5 mg/kg per body weight. An indicated daily dosagein the larger mammal, including, but not limited to, humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered individed doses, including, but not limited to, up to four times a day orin extended release form. Suitable unit dosage forms for oraladministration comprise from about 1 to 50 mg active ingredient. Theforegoing ranges are merely suggestive, as the number of variables inregard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Use of FLAP Modulators to Prevent and/or Treat Leukotriene-Dependent orLeukotriene Mediated Diseases or Conditions

The therapy of leukotriene-dependent or leukotriene mediated diseases orconditions is designed to modulate the activity of FLAP. Such modulationmay include, by way of example only, inhibiting or antagonizing FLAPactivity. For example, a FLAP inhibitor can be administered in order todecrease synthesis of leukotrienes within the individual, or possibly todownregulate or decrease the expression or availability of the FLAP mRNAor specific splicing variants of the FLAP mRNA. Downregulation ordecreasing expression or availability of a native FLAP mRNA or of aparticular splicing variant could minimize the expression or activity ofa defective nucleic acid or the particular splicing variant and therebyminimize the impact of the defective nucleic acid or the particularsplicing variant.

In accordance with one aspect, compositions and methods described hereininclude compositions and methods for treating, preventing, reversing,halting or slowing the progression of leukotriene-dependent orleukotriene mediated diseases or conditions once it becomes clinicallyevident, or treating the symptoms associated with or related toleukotriene-dependent or leukotriene mediated diseases or conditions, byadministering to the subject a compound described herein, orpharmaceutical composition or medicament which includes a compounddescribed herein. The subject may already have a leukotriene-dependentor leukotriene mediated disease or condition at the time ofadministration, or be at risk of developing a leukotriene-dependent orleukotriene mediated disease or condition. The symptoms ofleukotriene-dependent or leukotriene mediated diseases or conditions ina subject can be determined by one skilled in the art and are describedin standard textbooks.

The activity of 5-lipoxygenase activating protein in a mammal may bedirectly or indirectly modulated by the administration of (at leastonce) an effective amount of at least one compound of any of Formula(E), Formula (E-I), or Formula (E-II), or pharmaceutical composition ormedicament which includes a compound of any of Formula (E), Formula(E-I), or Formula (E-II), to a mammal. Such modulation includes, but isnot limited to, reducing and/or inhibiting the activity of5-lipoxygenase activating protein. In addition, the activity ofleukotrienes in a mammal may be directly or indirectly modulated,including reducing and/or inhibiting, by the administration of (at leastonce) an effective amount of at least one compound of any of Formula(E), Formula (E-I), or Formula (E-II), or pharmaceutical composition ormedicament which includes a compound of any of Formula (E), Formula(E-I), or Formula (E-II), to a mammal. Such modulation includes, but isnot limited to, reducing and/or inhibiting the activity of5-lipoxygenase activating protein.

Prevention and/or treatment leukotriene-dependent or leukotrienemediated diseases or conditions may comprise administering to a mammalat least once an effective amount of at least one compound of any ofFormula (E), Formula (E-I), or Formula (E-II), or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(E), Formula (E-I), or Formula (E-II). By way of example, the preventionand/or treatment of inflammation diseases or conditions may compriseadministering to a mammal at least once an effective amount of at leastone compound of any of Formula (E), Formula (E-I), or Formula (E-II), orpharmaceutical composition or medicament which includes a compound ofany of Formula (E), Formula (E-I), or Formula (E-II).Leukotriene-dependent or leukotriene mediated diseases or conditionsthat may be treated by a method comprising administering to a mammal atleast once an effective amount of at least one compound of any ofFormula (E), Formula (E-I), or Formula (E-II), or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(E), Formula (E-I), or Formula (E-II), include, but are not limited to,bone diseases and disorder, cardiovascular diseases and disorders,inflammatory diseases and disorders, dermatological diseases anddisorders, ocular diseases and disorders, cancer and other proliferativediseases and disorders, respiratory diseases and disorder, andnon-cancerous disorders.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound of any of Formula (E), Formula (E-I), orFormula (E-II), or pharmaceutical composition or medicament whichincludes a compound of any of Formula (E), Formula (E-I), or Formula(E-II). By way of example the respiratory disease may be asthma; seeRiccioni et al, Ann. Clin. Lab. Sci., v34, 379-387 (2004). In addition,the respiratory disease may include, but is not limited to, adultrespiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma,allergic rhinitis, vascular responses, endotoxin shock, fibrogenesis,pulmonary fibrosis, allergic diseases, chronic inflammation, and adultrespiratory distress syndrome.

By way of example only, included in such treatment methods are methodsfor preventing chronic obstructive pulmonary disease comprisingadministering to the mammal at least once an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II). Inaddition, chronic obstructive pulmonary disease includes, but is notlimited to, chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis.

By way of example only, included in such treatment methods are methodsfor preventing increased mucosal secretion and/or edema in a disease orcondition comprising administering to the mammal at least once aneffective amount of at least one compound of any of Formula (E), Formula(E-I), or Formula (E-II), or pharmaceutical composition or medicamentwhich includes a compound of any of Formula (E), Formula (E-I), orFormula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II); seeJala et al, Trends in Immunol., v25, 315-322 (2004) and Mehrabian et al,Curr. Opin. Lipidol., v14, 447-457 (2003).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing cardiac reperfusion injuryfollowing myocardial ischemia and/or endotoxic shock comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing the constriction of bloodvessels in a mammal comprising administering at least once to the mammalan effective amount of at least one compound of any of Formula (E),Formula (E-I), or Formula (E-II), or pharmaceutical composition ormedicament which includes a compound of any of Formula (E), Formula(E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering at least once to themammal an effective amount of at least one compound of any of Formula(E), Formula (E-I), or Formula (E-II), or pharmaceutical composition ormedicament which includes a compound of any of Formula (E), Formula(E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte recruitmentcomprising administering at least once to the mammal an effective amountof at least one compound of any of Formula (E), Formula (E-I), orFormula (E-II), or pharmaceutical composition or medicament whichincludes a compound of any of Formula (E), Formula (E-I), or Formula(E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering at least once to the mammal aneffective amount of at least one compound of any of Formula (E), Formula(E-I), or Formula (E-II), or pharmaceutical composition or medicamentwhich includes a compound of any of Formula (E), Formula (E-I), orFormula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering at least once to the mammal aneffective amount of at least one compound of any of Formula (E), Formula(E-I), or Formula (E-I), or pharmaceutical composition or medicamentwhich includes a compound of any of Formula (E), Formula (E-I), orFormula (E-II); see Lambiase et al, Arch. Opthalmol., v121, 615-620(2003).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing CNS disorders comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II). CNSdisorders include, but are not limited to, multiple sclerosis,Parkinson's disease, Alzheimer's disease, stroke, cerebral ischemia,retinal ischemia, post-surgical cognitive dysfunction, migraine,peripheral neuropathy/neuropathic pain, spinal cord injury, cerebraledema and head injury.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cancer comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II). Thetype of cancer may include, but is not limited to, pancreatic cancer andother solid or hematological tumors, see Poff and Balazy, Curr. DrugTargets Inflamm. Allergy, v3, 19-33 (2004) and Steele et al, CancerEpidemiology & Prevention, v8, 467-483 (1999).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing endotoxic shock and septicshock comprising administering at least once to the mammal an effectiveamount of at least one compound of any of Formula (E), Formula (E-I), orFormula (E-II), or pharmaceutical composition or medicament whichincludes a compound of any of Formula (E), Formula (E-I), or Formula(E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein methods for preventing rheumatoid arthritis andosteoarthritis comprising administering at least once to the mammal aneffective amount of at least one compound of any of Formula (E), Formula(E-I), or Formula (E-II), or pharmaceutical composition or medicamentwhich includes a compound of any of Formula (E), Formula (E-I), orFormula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing increased GI diseasescomprising administering at least once to the mammal an effective amountof at least one compound of any of Formula (E), Formula (E-I), orFormula (E-II), or pharmaceutical composition or medicament whichincludes a compound of any of Formula (E), Formula (E-I), or Formula(E-II). Such GI diseases include, by way of example only, inflammatorybowel disease (IBD), colitis and Crohn's disease.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the reduction of inflammation whilealso preventing transplant rejection or preventing or treating tumors oraccelerating the healing of wounds comprising administering at leastonce to the mammal an effective amount of at least one compound of anyof Formula (E), Formula (E-I), or Formula (E-II), or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(E), Formula (E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering at least once to the mammal an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating type II diabetes comprisingadministering to at least once to the mammal an effective amount of atleast one compound of any of Formula (E), Formula (E-I), or Formula(E-II), or pharmaceutical composition or medicament which includes acompound of any of Formula (E), Formula (E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating inflammatory responses of theskin comprising administering at least once to the mammal an effectiveamount of at least one compound of any of Formula (E), Formula (E-I), orFormula (E-II), or pharmaceutical composition or medicament whichincludes a compound of any of Formula (E), Formula (E-I), or Formula(E-II). Such inflammatory responses of the skin include, by way ofexample, psoriasis, dermatitis, contact dermatitis, eczema, urticaria,rosacea, wound healing and scarring. In another aspect are methods forreducing psoriatic lesions in the skin, joints, or other tissues ororgans, comprising administering at least once to the mammal aneffective amount of at least one compound of any of Formula (E), Formula(E-I), or Formula (E-II), or pharmaceutical composition or medicamentwhich includes a compound of any of Formula (E), Formula (E-I), orFormula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cystitis, including,by way of example only, interstitial cystitis, comprising administeringat least once to the mammal an effective amount of at least one compoundof any of Formula (E), Formula (E-I), or Formula (E-II), orpharmaceutical composition or medicament which includes a compound ofany of Formula (E), Formula (E-I), or Formula (E-II).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of metabolic syndromessuch as Familial Mediterranean Fever comprising administering at leastonce to the mammal an effective amount of at least one compound of anyof Formula (E), Formula (E-I), or Formula (E-II), or pharmaceuticalcomposition or medicament which includes a compound of any of Formula(E), Formula (E-I), or Formula (E-II).

Combination Treatments

In certain instances, it may be appropriate to administer at least onecompound of any of Formula (E), Formula (E-I), or Formula (E-II), incombination with another therapeutic agent. By way of example only, ifone of the side effects experienced by a patient upon receiving one ofthe compounds herein is inflammation, then it may be appropriate toadminister an anti-inflammatory agent in combination with the initialtherapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit of experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. By way of example only, in atreatment for asthma involving administration of one of the compoundsdescribed herein, increased therapeutic benefit may result by alsoproviding the patient with other therapeutic agents or therapies forasthma. In any case, regardless of the disease, disorder or conditionbeing treated, the overall benefit experienced by the patient may simplybe additive of the two therapeutic agents or the patient may experiencea synergistic benefit.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literature. Acombination treatment regimen may encompasses treatment regimens inwhich administration of a FLAP or 5-LO inhibitor described herein isinitiated prior to, during, or after treatment with a second agentdescribed above, and continues until any time during treatment with thesecond agent or after termination of treatment with the second agent. Italso includes treatments in which a FLAP or 5-LO inhibitor describedherein and the second agent being used in combination are administeredsimultaneously or at different times and/or at decreasing or increasingintervals during the treatment period. Combination treatment furtherincludes periodic treatments that start and stop at various times toassist with the clinical management of the patient. For example, a FLAPor 5-LO inhibitor described herein in the combination treatment can beadministered weekly at the onset of treatment, decreasing to biweekly,and decreasing further as appropriate.

Compositions and methods for combination therapy are provided herein. Inaccordance with one aspect, the pharmaceutical compositions disclosedherein are used to treat leukotriene-dependent or leukotriene mediatedconditions. In accordance with another aspect, the pharmaceuticalcompositions disclosed herein are used to treat respiratory diseases,where treatment with a FLAP inhibitor is indicated, in particularasthma, and to induce bronchodilation in a subject. In one embodiment,pharmaceutical compositions disclosed herein are used to treat a subjectsuffering from a vascular inflammation-driven disorder. In oneembodiment, the pharmaceutical compositions disclosed herein are used totreat a subject susceptible to myocardial infarction (MI).

Combination therapies described herein can be used as part of a specifictreatment regimen intended to provide a beneficial effect from theco-action of a FLAP inhibitors described herein and a concurrenttreatment. It is understood that the dosage regimen to treat, prevent,or ameliorate the condition(s) for which relief is sought, can bemodified in accordance with a variety of factors. These factors includethe type of respiratory disorder and the type of bronchodilation fromwhich the subject suffers, as well as the age, weight, sex, diet, andmedical condition of the subject. Thus, the dosage regimen actuallyemployed can vary widely and therefore can deviate from the dosageregimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is one of thecompounds described herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

In addition, the compounds described herein may also be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of any of Formula (E),Formula (E-I), or Formula (E-II), and/or combinations with othertherapeutics are combined with genetic testing to determine whether thatindividual is a carrier of a mutant gene that is known to be correlatedwith certain diseases or conditions.

The compounds described herein, and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over 5 minutes toabout 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from about 1month to about 3 months. The length of treatment can vary for eachsubject, and the length can be determined using the known criteria. Forexample, the compound or a formulation containing the compound can beadministered for at least 2 weeks, preferably about 1 month to about 5years, and more preferably from about 1 month to about 3 years.

By way of example, therapies which combine compounds of any of Formula(E), Formula (E-I), or Formula (E-II), with inhibitors of leukotrienesynthesis or leukotriene receptor antagonists, either acting at the sameor other points in the leukotriene synthesis pathway, could prove to beparticularly useful for treating leukotriene-dependent or leukotrienemediated diseases or conditions. In addition, by way of example,therapies which combine compounds of any of Formula (E), Formula (E-I),or Formula (E-II), with inhibitors of inflammation could prove to beparticularly useful for treating leukotriene-dependent or leukotrienemediated diseases or conditions.

Anti-Inflammatory Agents

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with ananti-inflammatory agent including, but not limited to, arthrotec,asacol, auralglan, azulfidine, daypro, etodolac, ponstan, salofalk, andsolumedrol; non-steroidal anti-inflammatory agents, by way of example,aspirin (Bayer™, Bufferin™), indomethacin (Indocin™), rofecoxib(Vioxx™), celecoxib (Celebrex™), valdecoxib (Bextra™), diclofenac,etodolac, ketoprofen, Iodine, mobic, nabumetone, naproxen, piroxicam;and corticosteroids, by way of example, celestone, prednisone, anddeltasone. Corticosteroids do not directly inhibit leukotrieneproduction, therefore co-dosing with steroids could provide additionalanti-inflammatory benefit.

By way of example, asthma is a chronic inflammatory diseasecharacterized by pulmonary eosinophilia and airway hyperresponsiveness.Zhao et al., Proteomics, Jul. 4, 2005. In patients with asthma,leukotrienes may be released from mast cells, eosinophils, andbasophils. The leukotrienes are involved in contraction of airway smoothmuscle, an increase in vascular permeability and mucus secretions, andhave been reported to attract and activate inflammatory cells in theairways of asthmatics (Siegel et al., ed., Basic Neurochemistry,Molecular, Cellular and Medical Aspects, Sixth Ed., Lippincott Williams& Wilkins, 1999). Thus, in another embodiment described herein, themethods for treatment of respiratory diseases includes administration toa patient compounds, pharmaceutical compositions, or medicamentsdescribed herein in combination with an anti-inflammatory agent.

Leukotriene Receptor Antagonists

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination withleukotriene receptor antagonists including, but are not limited to,CysLT₁/CysLT₂ dual receptor antagonists and CysLT₁ receptor antagonists.In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with aCysLT₁/CysLT₂ dual receptor antagonist. CysLT₁/CysLT₂ dual receptorantagonists include, but are not limited to, BAY u9773, Cuthbert et alEP 00791576 (published 27 Aug. 1997), DUO-LT (Galczenski et al, D38,Poster F4 presented at American Thoracic Society, May 2002) and Tsuji etal, Org. Biomol. Chem., 1, 3139-3141, 2003. For a particular patient,the most appropriate formulation or method of use of such combinationtreatments may depend on the type of leukotriene-dependent orleukotriene mediated disorder, the time period in which the FLAPinhibitor acts to treat the disorder and the time period in which theCysLT₁/CysLT₂ dual receptor antagonist acts to inhibit CysLT receptoractivity. By way of example only, such combination treatments may beused for treating a patient suffering from a respiratory disorders.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with aCysLT₁ receptor antagonist. CysLT₁ receptor antagonists include, but arenot limited to, Zafirlukast (“Accolate™”), Montelukast (“Singulair™”),Prankulast (“Onon™”), and derivatives or analogs thereof. Suchcombinations may be used to treat leukotriene-dependent or leukotrienemediated disorder, including respiratory disorders.

The co-administration of a FLAP or 5-LO inhibitor described herein witha CysLT₁ receptor antagonist or a dual CysLT₁/CysLT₂ receptor antagonistmay have therapeutic benefit over and above the benefit derived from theadministration of a either a FLAP or 5-LO inhibitor or a CysLT₁Rantagonist alone. In the case that substantial inhibition of leukotrieneproduction has undesired effects, partial inhibition of this pathwaythrough the amelioration of the effects of the proinflammatory LTB₄ andcysteinyl leukotrienes combined with the block of the CysLT₁ receptorand/or dual CysLT₁/CysLT₂ receptor block may afford substantialtherapeutic benefits, particularly for respiratory diseases.

Other Combination Therapies

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as proliferative disorders, including cancer, comprisesadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with at least one additionalagent selected from the group consisting of alemtuzumab, arsenictrioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab,platinum-based compounds such as cisplatin, cladribine,daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine,5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™, taxol,temozolomide, thioguanine, or classes of drugs including hormones (anantiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of transplanted organs or tissues or cells,comprises administration to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with atleast one additional agent selected from the group consisting ofazathioprine, a corticosteroid, cyclophosphamide, cyclosporin,dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus,thymoglobulin.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as atherosclerosis, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from thegroup consisting of HMG-CoA reductase inhibitors (e.g., statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin;simvastatin; dihydroxy open-acid simvastatin, particularly the ammoniumor calcium salts thereof; pravastatin, particularly the sodium saltthereof; fluvastatin, particularly the sodium salt thereof,atorvastatin, particularly the calcium salt thereof; nisvastatin, alsoreferred to as NK-104; rosuvastatin); agents that have bothlipid-altering effects and other pharmaceutical activities; HMG-CoAsynthase inhibitors; cholesterol absorption inhibitors such asezetimibe; cholesterol ester transfer protein (CETP) inhibitors, forexample JTT-705 and CP529, 414; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors);acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors, forexample glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists, including the compounds commonly referred to as glitazones,for example troglitazone, pioglitazone and rosiglitazone and includingthose compounds included within the structural class known asthiazolidinediones as well as those PPARγ agonists outside thethiazolidinedione structural class; PPARα agonists such as clofibrate,fenofibrate including micronized fenofibrate, and gemfibrozil; PPAR dualα/γ agonists such as5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,known as KRP-297; vitamin B6 (also known as pyridoxine) and thepharmaceutically acceptable salts thereof such as the HCl salt; vitaminB12 (also known as cyanocobalamin); folic acid or a pharmaceuticallyacceptable salt or ester thereof such as the sodium salt and themethylglucamine salt; anti-oxidant vitamins such as vitamin C and E andbeta carotene; beta-blockers; angiotensin II antagonists such aslosartan; angiotensin converting enzyme inhibitors such as enalapril andcaptopril; calcium channel blockers such as nifedipine and diltiazam;endothelian antagonists; agents that enhance ABC1 gene expression; FXRand LXR ligands including both inhibitors and agonists; bisphosphonatecompounds such as alendronate sodium; and cyclooxygenase-2 inhibitorssuch as rofecoxib and celecoxib.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of stroke, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from COX-2inhibitors; nitric oxide synthase inhibitors, such asN-(3-(aminomethyl)benzyl)acetamidine; Rho kinase inhibitors, such asfasudil; angiotension II type-i receptor antagonists, includingcandesartan, losartan, irbesartan, eprosartan, telmisartan andvalsartan; glycogen synthase kinase 3 inhibitors; sodium or calciumchannel blockers, including crobenetine; p38 MAP kinase inhibitors,including SKB 239063; thromboxane AX-synthetase inhibitors, includingisbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductaseinhibitors), including lovastatin, simvastatin, dihydroxy open-acidsimvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, androsuvastatin; neuroprotectants, including free radical scavengers,calcium channel blockers, excitatory amino acid antagonists, growthfactors, antioxidants, such as edaravone, vitamin C, TROLOX™, citicolineand minicycline, and reactive astrocyte inhibitors, such as(2R)-2-propyloctanoic acid; beta andrenergic blockers, such aspropranolol, nadolol, timolol, pindolol, labetalol, metoprolol,atenolol, esmolol and acebutolol; NMDA receptor antagonists, includingmemantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists;receptor platelet fibrinogen receptor antagonists, including tirofibanand lamifiban; thrombin inhibitors; antithrombotics, such as argatroban;antihypertensive agents, such as enalapril; vasodilators, such ascyclandelate; nociceptin antagonists; DPIV antagonists; GABA 5 inverseagonists; and selective androgen receptor modulators.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of pulmonary fibrosis, comprises administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected fromanti-inflammatory agents, such as corticosteroids, azathioprine orcyclophosphamide.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of interstitial cystitis, comprises administrationto a patient compounds, pharmaceutical compositions, or medicamentsdescribed herein in combination with at least one additional agentselected from dimethylsulfoxide, omalizumab, and pentosan polysulfate.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of disorders of bone, comprises administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected fromthe group consisting of minerals, vitamins, bisphosphonates, anabolicsteroids, parathyroid hormone or analogs, and cathepsin K inhibitors.

Treatment of Leukotriene Based Conditions or Diseases usingCysLT₁/CysLT₂ Receptor Antagonists

In accordance with another aspect, the compositions and methodsdescribed herein are designed to deliver a CysLT₁/CysLT₂ dual receptorantagonist to block the CysLT receptor activity. The term “CysLTantagonist” or “CysLT receptor antagonist” or “leukotriene receptorantagonist” refers to a therapy that decreases the signaling of CysLTsthrough CysLT receptors. CysLT typically refers to either LTC₄, LTD₄ orLTE₄. Cysteinyl leukotrienes are potent smooth muscle constrictingagents, particularly in respiratory and circulatory systems. These aremediated via at least two cell receptors, CysLT₁ and CysLT₂. The CysLT₁receptor and CysLT₂ receptors are G-protein-coupled receptors with sevenputative transmembrane regions and an intracellular domain thatinteracts with G-proteins, Evans et al, Prostaglandins and Other LipidMediators, 68-69, p 587-597, (2002). Examples of CysLT₁/CysLT₂ dualreceptor antagonists are BAY u9773, Cuthbert et al EP 00791576(published 27 Aug. 1997), DUO-LT (Galczenski et al, D38, Poster F4presented at American Thoracic Society, May 2002) and Tsuji et al, Org.Biomol. Chem., 1, 3139-3141, 2003.

In certain embodiments, methods for treatment of leukotriene-dependentor leukotriene mediated diseases or conditions includes administering topatients compounds, pharmaceutical compositions, or medicamentscomprising a CysLT₁/CysLT₂ receptor antagonist. By way of example, suchcompounds, pharmaceutical compositions, or medicaments may be used astreatment and/or prevention for respiratory diseases including, but notlimited to, chronic stable asthma.

Diagnostic Methods for Patient Identification

The screening of “leukotriene-responsive patients” which may be selectedfor treatment with compounds of any of Formula (E), Formula (E-I), orFormula (E-II), or pharmaceutical compositions or medicaments describedherein which include compounds of any of Formula (E), Formula (E-I), orFormula (E-II), or other FLAP modulators, may be accomplished usingtechniques and methods described herein. Such techniques and methodsinclude, by way of example, evaluation of gene haplotypes (genotypeanalysis), monitoring/measurement of biomarkers (phenotype analysis),monitoring/measurement of functional markers (phenotype analysis), whichindicate patient response to known modulators of the leukotrienepathway, or any combination thereof.

Genotype Analysis: FLAP Polymorphisms

Human FLAP has been purified and cloned and is an 18 kilodaltonmembrane-bound protein which is most highly expressed in humanneutrophils. The FLAP gene is located at 13q12 and the gene has beenlinked to increased risk for both myocardial infarction and stroke inseveral populations. A number of polymorphisms and haplotypes in thegene encoding FLAP have been identified in individuals (U.S. PatentApplication 2005113408; Sayers, Clin. Exp. Allergy, 33(8):1103-10, 2003;Kedda, et al., Clin. Exp. Allergy, 35(3):332-8, 2005). Particular FLAPhaplotypes have been linked to myocardial infarction and stroke inseveral populations (Helgadottir A et al. Nature Genet. 36:233-239(2004); Helgadottir A et al. Am J Hum Genet 76:505-509 (2004);Lohmussaar E et al. Stroke 36: 731-736 (2005); Kajimoto K et al. Circ J69:1029-1034 (2005). Previously, polymorphisms in certain genes havebeen demonstrated to correlate with responsiveness to given therapies,for example, the responsiveness of cancers to particularchemotherapeutic agents (Erichsen, et al., Br. J. Cancer, 90(4):747-51,2004; Sullivan, et al., Oncogene, 23(19):3328-37, 2004). Therefore,patients who are under consideration for treatment with the novel FLAPinhibitors described herein, or drug combinations that include suchnovel FLAP inhibitors, may be screened for potential responsiveness totreatment based on their FLAP polymorphisms, or haplotypes.

Additionally, polymorphisms in any of the synthetic or signaling genesdedicated to the leukotriene pathway could result in a patient who ismore responsive or less responsive to leukotriene modulator therapy(either FLAP or 5-LO inhibitor or leukotriene receptor antagonists). Thegenes dedicated to the leukotriene pathway are 5-lipoxygenase,5-lipoxygenase-activating protein, LTA₄ hydrolase, LTC₄ synthase, LTB₄receptor 1 (BLT₁), LTB₄ receptor 2 (BLT₂), cysteinyl leukotrienereceptor 1 (CysLT₁R), cysteinyl leukotriene receptor 2 (CysLT₂R). Forexample, the 5-LO gene has been linked to aspirin intolerant asthma andairway hyperresponsiveness (Choi S H et al. Hum Genet. 114:337-344(2004); Kim, S H et al. Allergy 60:760-765 (2005). Genetic variants inthe promoter region of 5-LO have been shown to predict clinicalresponses to a SLO inhibitor in asthmatics (Drazen et al, NatureGenetics, 22, p 168-170, (1999). The LTC₄ synthase gene has been linkedto atopy and asthma (Moissidis I et al. Genet Med 7:406-410 (2005). TheCysLT₂ receptor has been linked to asthma and atopy (Thompson M D et al.Pharmacogenetics 13:641-649 (2003); Pillai S G et al. Pharmacogenetics14:627-633 (2004); Park J S et al. Pharmacogenet Genomics 15:483-492(2005); Fukai H et al. Pharmacogenetics 14:683-690 (2004). Anypolymorphisms in any leukotriene pathway gene or combination ofpolymorphisms or haplotypes may result in altered sensitivity of thepatient to therapy aimed at reducing the pathological effects ofleukotrienes. Selection of patients who might best respond to theleukotriene modulator therapies described herein may include knowledgeof polymorphisms in the leukotriene pathway genes and also knowledge ofthe expression of leukotriene-driven mediators. Patient selection couldbe made on the basis of leukotriene pathway genotype alone, phenotypealone (biomarkers or functional markers) or any combination of genotypeand phenotype.

A “haplotype,” as described herein, refers to a combination of geneticmarkers (“alleles”). A haplotype can comprise one or more alleles (e.g.,a haplotype containing a single SNP), two or more alleles, three or morealleles, four or more alleles, or five or more alleles. The geneticmarkers are particular “alleles” at “polymorphic sites” associated withFLAP. A nucleotide position at which more than one sequence is possiblein a population is referred to herein as a “polymorphic site.” Where apolymorphic site is a single nucleotide in length, the site is referredto as a single nucleotide polymorphism (“SNP”). For example, if at aparticular chromosomal location, one member of a population has anadenine and another member of the population has a thymine at the sameposition, then this position is a polymorphic site, and, morespecifically, the polymorphic site is a SNP. Polymorphic sites can allowfor differences in sequences based on substitutions, insertions ordeletions. Each version of the sequence with respect to the polymorphicsite is referred to herein as an “allele” of the polymorphic site. Thus,in the previous example, the SNP allows for both an adenine allele and athymine allele.

Typically, a reference sequence is referred to for a particularsequence. Alleles that differ from the reference are referred to as“variant” alleles. The term “variant FLAP” as used herein, refers to asequence that differs from a reference FLAP sequence, but is otherwisesubstantially similar. The genetic markers that make up the haplotypesdescribed herein are FLAP variants. In certain embodiments the FLAPvariants are at least about 90% similar to a reference sequence. Inother embodiments the FLAP variants are at least about 91% similar to areference sequence. In other embodiments the FLAP variants are at leastabout 92% similar to a reference sequence. In other embodiments the FLAPvariants are at least about 93% similar to a reference sequence. Inother embodiments the FLAP variants are at least about 94% similar to areference sequence. In other embodiments the FLAP variants are at leastabout 95% similar to a reference sequence. In other embodiments the FLAPvariants are at least about 96% similar to a reference sequence. Inother embodiments the FLAP variants are at least about 97% similar to areference sequence. In other embodiments the FLAP variants are at leastabout 98% similar to a reference sequence. In other embodiments the FLAPvariants are at least about 99% similar to a reference sequence.

Additionally, in certain embodiments the FLAP variants differ from thereference sequence by at least one base, while in other embodiments theFLAP variants differ from the reference sequence by at least two bases.In other embodiments the FLAP variants differ from the referencesequence by at least three bases, and in still other embodiments theFLAP variants differ from the reference sequence by at least four bases.

Additional variants can include changes that affect a polypeptide, e.g.,the FLAP polypeptide. The polypeptide encoded by a reference nucleotidesequence is the “reference” polypeptide with a particular referenceamino acid sequence, and polypeptides encoded by variant alleles arereferred to as “variant” polypeptides with variant amino acid sequences.The FLAP nucleic acid sequence differences, when compared to a referencenucleotide sequence, can include the insertion or deletion of a singlenucleotide, or of more than one nucleotide, resulting in a frame shift;the change of at least one nucleotide, resulting in a change in theencoded amino acid; the change of at least one nucleotide, resulting inthe generation of a premature stop codon; the deletion of severalnucleotides, resulting in a deletion of one or more amino acids encodedby the nucleotides; the insertion of one or several nucleotides, such asby unequal recombination or gene conversion, resulting in aninterruption of the coding sequence; duplication of all or a part of asequence; transposition; or a rearrangement of a nucleotide sequence, asdescribed in detail above. Such sequence changes alter the polypeptideencoded by a FLAP nucleic acid. For example, if the change in thenucleic acid sequence causes a frame shift, the frame shift can resultin a change in the encoded amino acids, and/or can result in thegeneration of a premature stop codon, causing generation of a truncatedpolypeptide.

By way of example, a polymorphism associated with a susceptibility tomyocardial infarction (MI), acute coronary syndrome (ACS), stroke orperipheral arterial occlusive disease (PAOD) can be a synonymous changein one or more nucleotides (i.e., a change that does not result in achange in the amino acid sequence). Such a polymorphism can, forexample, alter splice sites, decrease or increase expression levels,affect the stability or transport of mRNA, or otherwise affect thetranscription or translation of the polypeptide. The haplotypesdescribed below are found more frequently in individuals with MI, ACS,stroke or PAOD than in individuals without MI, ACS, stroke or PAOD.Therefore, these haplotypes may have predictive value for detecting asusceptibility to MI, ACS, stroke or PAOD in an individual.

Several variants of the FLAP gene have been reported to correlate withthe incidence of myocardial infarction in patients (1Hakonarson, JAMA,293(18):2245-56, 2005), plus FLAP gene markers reportedly associatedwith the risk for developing asthma have been described in U.S. Pat. No.6,531,279. Methods for identifying FLAP sequence variants are described,e.g., in U.S. Publication No. 2005/0113408, and in U.S. Pat. No.6,531,279, incorporated herein by reference herein in their entirety.

By way of example only, a haplotype associated with a susceptibility tomyocardial infarction or stroke comprises markers SG13S99, SG13S25,SG13S377, SG13S106, SG13S32 and SG13S35 at the 13q12-13 locus. Or, thepresence of the alleles T, G, G, G, A and G at SG13S99, SG13S25,SG13S377, SG13S106, SG13S32 and SG13S35, respectively (the B6haplotype), is diagnostic of susceptibility to myocardial infarction orstroke. Or, a haplotype associated with a susceptibility to myocardialinfarction or stroke comprises markers SG13S99, SG13S25, SG13S106,SG13S30 and SG13S42 at the 13q12-13 locus. Or, the presence of thealleles T, G, G, G and A at SG13S99, SG13S25, SG13S106, SG13S30 andSG13S42, respectively (the B5 haplotype), is diagnostic ofsusceptibility to myocardial infarction or stroke Or, a haplotypeassociated with a susceptibility to myocardial infarction or strokecomprises markers SG13S25, SG13S106, SG13S30 and SG13S42 at the 13q12-13locus. Or, the presence of the alleles G, G, G and A at SG13S25,SG13S106, SG13S30 and SG13S42, respectively (the B4 haplotype), isdiagnostic of susceptibility to myocardial infarction or stroke. Or, ahaplotype associated with a susceptibility to myocardial infarction orstroke comprises markers SG13S25, SG13S106, SG13S30 and SG13S32 at the13q12-13 locus. Or, the presence of the alleles G, G, G and A at SG13S25, SG13S106, SG13S30 and SG13S32, respectively (the Bs4 haplotype), isdiagnostic of susceptibility to myocardial infarction or stroke. In suchembodiments just described, patients who are under consideration fortreatment with compounds of any of Formula (E), Formula (E-I), orFormula (E-I), or drug combinations described herein that includecompounds of any of Formula (E), Formula (E-I), or Formula (E-II), maybe screened for potential responsiveness to treatment with compounds ofany of Formula (E), Formula (E-I), or Formula (E-II), based on suchhaplotypes.

By way of example only, a haplotype associated with a susceptibility tomyocardial infarction or stroke comprises markers SG13S99, SG13S25,SG13S114, G513S89 and SG13S32 at the 13q12-13 locus. Or, the presence ofthe alleles T, G, T, G and A at SG13S99, SG13S25, SG13S114, SG13S89 andSG13S32, respectively (the A5 haplotype), is diagnostic ofsusceptibility to myocardial infarction or stroke. Or, a haplotypeassociated with a susceptibility to myocardial infarction or strokecomprises markers SG13S25, SG13S114, SG13S89 and SG13S32 at the 13q12-13locus. Or, the presence of the alleles G, T, G and A at SG13525,SG13S114, SG13S89 and SG13S32, respectively (the A4 haplotype), isdiagnostic of susceptibility to myocardial infarction or stroke. In suchembodiments just described, patients who are under consideration fortreatment with compounds of any of Formula (E), Formula (E-I), orFormula (E-II), or drug combinations described herein that includecompounds of any of Formula (E), Formula (E-I), or Formula (E-II), maybe screened for potential responsiveness to treatment with compounds ofany of Formula (E), Formula (E-I), or Formula (E-II), based on suchhaplotypes.

Detecting haplotypes can be accomplished by methods known in the art fordetecting sequences at polymorphic sites, and therefore patients may beselected using genotype selection of FLAP, 5-LO or other leukotrienepathway gene polymorphisms. The presence or absence of a leukotrienepathway gene polymorphism or haplotype can be determined by variousmethods, including, for example, using enzymatic amplification,restriction fragment length polymorphism analysis, nucleic acidsequencing, electrophoretic analysis of nucleic acid from theindividual, or any combination thereof. In certain embodiments,determination of a SNP or haplotype may identify patients who willrespond to, or gain benefit from, treatment with compounds of any ofFormula (E), Formula (E-I), or Formula (E-II). By way of example,methods of diagnosing a susceptibility to myocardial infarction orstroke in an individual, comprises determining the presence or absenceof certain single nucleotide polymorphisms (SNPs) or of certainhaplotypes, wherein the presence of the SNP or the haplotype isdiagnostic of susceptibility to myocardial infarction or stroke.

Phenotype Analysis: Biomarkers

Patients who are under consideration for treatment with compoundsdescribed herein, or drug combinations described herein that includecompounds described herein, may be screened for potential responsivenessto treatment based on leukotriene-driven inflammatory biomarkerphenotypes.

Patient screening based on leukotriene-driven inflammatory biomarkerphenotypes may be used as an alternative to, or it may be complimentarywith, patient screening by leukotriene pathway gene haplotype detection.The term “biomarker” as used herein refers to a characteristic which canbe measured and evaluated as an indicator of normal biologicalprocesses, pathological processes, or pharmacological responses totherapeutic intervention. Thus a biomarker may be any substance,structure or process which can be measured in the body, or its products,and which may influence or predict the incidence of outcome or disease.Biomarkers may be classified into markers of exposure, effect, andsusceptibility. Biomarkers can be physiologic endpoints, by way ofexample blood pressure, or they can be analytical endpoints, by way ofexample, blood glucose, or cholesterol concentrations. Techniques, usedto monitor and/or measure biomarkers include, but are not limited to,NMR, LC-MS, LC-MS/MS, GC-MS, GC-MS/MS, HPLC-MS, HPLC-MS/MS, FT-MS,FT-MS/MS, ICP-MS, ICP-MS/MS, peptide/protein sequencing, nucleic acidsequencing, electrophoresis techniques, immuno-assays, immuno-blotting,in-situ hybridization, fluorescence in-situ hybridization, PCR,radio-immuno assays, and enzyme-immuno assays. Single nucleotidepolymorphisms (SNPs) have also been useful for the identification ofbiomarkers for propensity to certain diseases and also susceptibility orresponsiveness to drugs such as chemotherapeutic agents and antiviralagents. These techniques, or any combination thereof, may be used toscreen patients for leukotriene-dependent or leukotriene mediateddiseases or conditions, wherein such patients may be beneficiallytreated with compounds described herein, or drug combinations describedherein that include compounds described herein.

By way of example only, patients may be selected for treatment withcompounds described herein, or drug combinations described herein thatinclude compounds described herein, by screening for enhancedinflammatory blood biomarkers such as, but not limited to, stimulatedLTB₄, LTC₄, LTE₄, myeloperoxidase (MPO), eosinophil peroxidase (EPO),C-reactive protein (CRP), soluble intracellular adhesion molecule(sICAM), monocyte chemoattractant protein (14CP-1), monocyteinflammatory protein (MIP-1α), interleukin-6 (IL-6), the TH2 T cellactivators interleukin 4 (IL-4), and 13 (IL-13) and other inflammatorycytokines. In certain embodiments, patients with inflammatoryrespiratory diseases, including but not limited to, asthma and COPD, orwith cardiovascular diseases, are selected as those most likely to beresponsive to leukotriene synthesis inhibition using compounds of any ofFormula (E), Formula (E-I), or Formula (E-II), by using a panel ofleukotriene driven inflammatory biomarkers.

Phenotpe-Analysis: Functional Markers

Patients who are under consideration for treatment with compoundsdescribed herein, or drug combinations described herein that includecompounds described herein, may be screened for response to knownmodulators of the leukotriene pathway. Patient screening by evaluationof functional markers as indicators of a patient's response to knownmodulators of the leukotriene pathway may be used as an alternative to,or it may be complimentary with, patient screening by leukotrienepathway gene haplotype detection (genotype analysis) and/ormonitoring/measurement of leukotriene-driven inflammatory biomarkerphenotypes. Functional markers may include, but are not limited to, anyphysical characteristics associated with a leukotriene dependentcondition or disease, or knowledge of current or past drug treatmentregimens.

By way of example only, the evaluation of lung volume and/or functionmay be used as a functional marker for leukotriene-dependent orleukotriene mediated diseases or conditions, such as respiratorydiseases. Lung, function tests may be used to screen patients, with suchleukotriene-dependent or leukotriene mediated diseases or conditions,for treatment using compounds described herein, or pharmaceuticalcompostions or medicaments which include compounds described herein.Such tests include, but are not limited to, evaluation of lung volumesand capacities, such as tidal volume, inspiratory reserve volume,expiratory reserve volume, residual volume, inspiratory capacity,functional residual capacity, vital capacity, total lung capacity,respiratory minute volume, alveolar ventilation, timed vital capacity,and ventilatory capacity. Method of measurement of lung volumes andcapacities include, but are not limited to, maximum expiratory flowvolume curve, forced expiratory volume in 1 sec. (FEV1), peak expiratoryflow rate. In addition, other lung function tests used as functionalmarkers for patient evaluation described herein include, but are notlimited to, respiratory muscle power, maximum inspiratory pressure,maximum expiratory pressure, transdiaphragmatic pressure, distributionof ventilation, single breath nitrogen test, pulmonary nitrogen washout;and gas transfer.

Additionally, the knowledge of a patients past or current treatmentregimen may be used as a functional marker to assist in screeningpatients for treatment of leukotriene dependent conditions or diseasesusing compounds described herein, or pharmaceutical compositions ormedicaments which include compounds described herein. By way of exampleonly, such treatment regimens may include past or current treatmentusing zileuton (Zyflo™), montelukast (Singulair™), pranlukast (Onon™),zafirlukast (Accolate™).

Also, patients who are under consideration for treatment with compoundsdescribed herein, or drug combinations described herein that includecompounds described herein, may be screened for functional markers whichinclude, but are not limited to, reduced eosinophil and/or basophil,and/or neutrophil, and/or monocyte and/or dendritic cell and/orlymphocyte recruitment, decreased mucosal secretion, decreased mucosaledema, and/or increased bronchodilation.

Methods for the identification of a patient in need of treatment forleukotriene-dependent or leukotriene mediated conditions or diseases,and exemplary, non-limiting treatment methods are shown in FIG. 12, FIG.13 and FIG. 14, wherein a patient sample is analyzed and the informationobtained is used to identify possible treatment methods. It is expectedthat one skilled in the art will use this information in conjunctionwith other patient information, including, but not limited to age,weight, sex, diet, and medical condition, to choose a treatment method.It is also expected that each piece of information will be given aparticular weight in the decision process. In certain embodiments, theinformation obtained from the diagnostic methods described above and anyother patient information, including, but not limited to age, weight,sex, diet, and medical condition, are incorporated into an algorithmused to elucidate a treatment method, wherein each piece of informationwill be given a particular weight in the decision process.

In certain embodiments a patient sample is analyzed for leukotriene genehaplotypes, by way of example only, FLAP haplotypes, and the informationobtained identifies a patient in need of treatment using varioustreatment methods. Such treatment methods include, but are not limitedto, administering a therapeutic effective amount of a compound describedherein, or pharmaceutical composition or medicament which includes acompound described herein, administering a therapeutic effective amountof a compound described herein, or pharmaceutical composition ormedicament which includes a compound described herein, in combinationwith a therapeutic effective amount of a leukotriene receptor antagonist(by way of example, CysLT₁/CysLT₂ antagonist or CysLT₁ antagonist), oradministering a therapeutic effective amount of a compound describedherein, or pharmaceutical composition or medicament which includes acompound described herein, in combination with a therapeutic effectiveamount of another anti-inflammatory agent. In other embodiments apatient sample is analyzed for leukotriene gene haplotypes, by way ofexample only, FLAP haplotypes, and/or phenotype biomarkers, and/orphenotype functional marker responses to leukotriene modifying agents.The patient may then be treated using various treatment methods. Suchtreatment methods include, but are not limited to, administering atherapeutic effective amount of a compound described herein, orpharmaceutical composition or medicament which includes a compounddescribed herein, administering a therapeutic effective amount of acompound described herein, or pharmaceutical composition or medicamentwhich includes a compound described herein, in combination with atherapeutic effective amount of a leukotriene receptor antagonist (byway of example, CysLT₁/CysLT₂ antagonist or CysLT₁ antagonist), oradministering a therapeutic effective amount of a compound describedherein, or pharmaceutical composition or medicament which includes acompound described herein, in combination with a therapeutic effectiveamount of another anti-inflammatory agent. In still other embodiments apatient sample is analyzed for leukotriene gene haplotypes, by way ofexample only, FLAP haplotypes, and phenotype biomarkers, and phenotypefunctional marker responses to leukotriene modifying agents. The patientmay then be treated using various treatment methods. Such treatmentmethods include, but are not limited to, administering a therapeuticeffective amount of a FLAP inhibitor, or pharmaceutical composition ormedicament which includes a FLAP inhibitor, administering a therapeuticeffective amount of a FLAP inhibitor, or pharmaceutical composition ormedicament which includes a FLAP inhibitor, in combination with atherapeutic effective amount of a leukotriene receptor antagonist (byway of example, CysLT₁/CysLT₂ antagonist or CysLT₁ antagonist), oradministering a therapeutic effective amount of a FLAP inhibitor, orpharmaceutical composition or medicament which includes a FLAPinhibitor, in combination with a therapeutic effective amount of anotheranti-inflammatory agent.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may comprise one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself, a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Preparation of Intermediates Used in the Synthesis of Compounds ofFormula (E), Formula (E-I), and Formula (E-II)

Starting materials and intermediates used in the synthesis of compoundsof Formula (E), Formula (E-I), and Formula (E-II) are commerciallyavailable or can be synthesized by synthetic methods known in the art ordescribed herein. The preparation of intermediates, such as, forexample, those shown in Table 5, which are used herein and notcommercially available is described below. Other intermediates notspecifically mentioned herein and used in the synthesis of compounds ofFormula (E), Formula (E-I), and Formula (E-II), can be prepared usingthe methods described herein or known in the art.

TABLE 5 Intermediates used in the Synthesis of Compounds of Formula (E),Formula (E-I), and Formula (E-II) Compound # Structure Compound NameMethod for Preparation Int-5

C-(Di-imidazol-1-yl)- methyleneamine Route 8, Step 1 Int-10

3-Bromomethyl-azetidine-1- carboxylic acid tert-butyl ester Route 1,Steps 1-3a SM: 3-Azetidinecarboxylic acid (Sigma Aldrich) Int-19

2-Chloro-N-cyclopropyl-acetamide Route 2, Step 1 SM: Cyclopropylamine(Sigma Aldrich) Int-20

2-Chloromethyl-1,4,5,6-tetrahydro- pyrimidine Hydrochloride Route 3,Steps 1-2 SM: Chloro- acetonitrile (Sigma Aldrich) Int-21

(S)-2-(Toluene-4- sulfonyloxymethyl)-pyrrolidine-1- carboxylic acidtert-butyl ester Route 1, Step 3c SM: (S)-(−)-1-(tert-Butoxycarbonyl)-2-pyrroli dinemethanol (Sigma Aldrich) Int-22

(R)-2-(Toluene-4- sulfonyloxymethyl)-pyrrolidine-1- carboxylic acidtert-butyl ester Route 1, Step 3c SM: (R)-(+)-1-(tert-Butoxycarbonyl)-2-pyrroli dinemethanol (Sigma Aldrich) Int-23

(S)-2-Methanesulfonyloxymethyl- piperidine-1-carboxylic acid tert- butylester Route 1, Step 3d SM: 1-Boc-(S)-2- piperidinemethanol (Chem Impex)Int-24

Toluene-4-sulfonic acid (S)-5-oxo- pyrrolidin-2-ylmethyl ester Route 1,Step 3c SM: (S)-(+)-5- (Hydroxymethyl)-2- pyrrolidinone (Sigma Aldrich)Int-25

Toluene-4-sulfonic acid (R)-5-oxo- pyrrolidin-2-ylmethyl ester;6-27-Route 1, Step 3c SM: (R)-(−)-5- (Hydroxymethyl)-2- pyrrolidinone(Acros Organics) Int-27

3-Chloromethyl-5-methyl- isoxazole Hydrochloride Route 4, Step 4 SM:(5-Methylisoxazol-3- yl)methanol (Acros Organics) Int-28

3-Chloromethyl-1,5-dimethyl-1H- pyrazole Hydrochloride Route 4, Step 4SM: (1,5-Dimethyl-1H- pyrazol-3-yl)methanol (Acros Organics) Int-29

5-Chloromethyl-1,3-dimethyl-1H- pyrazole Hydrochloride Route 4, Step 4SM: (1,3-Dimethyl-1H- pyrazol-5-yl)methanol (Acros Organics) Int-30

2-(Toluene-4-sulfonyloxymethyl)- 2,3-dihydro-indole-1-carboxylic acidtert-butyl ester Route 1, Steps 1-3c SM: Indoline-2-carboxylic Acid(Sigma Aldrich) Int-31

(S)-2-(Toluene-4- sulfonyloxymethyl)-2,3-dihydro- indole-1-carboxylicacid tert-butyl ester Route 1, Steps 1, 3c SM: (S)-(+)-2-Indolinemethanol (Sigma Aldrich) Int-32

2-Chloromethyl-imidazo[1,2- a]pyridine Route 4, Step 4 SM:Imidazo[1,2-a]pyridin- 2-ylmethanol (Acros Organics) Int-33

Toluene-4-sulfonic acid (S)-2-tert- butoxycarbonylamino-2-phenyl- ethylester Route 1, Steps 1, 3c SM: (S)-(+)-2- Phenylglycinol (Sigma Aldrich)Int-34

Toluene-4-sulfonic acid (R)-2-tert- butoxycarbonylamino-2-phenyl- ethylester Route 1, Step 3c SM: (R)-(−)-N-(tert- Butoxycarbonyl)-2-phenylglycinol (Sigma Aldrich) Int-38

2-Chloro-N-(4-fluoro-phenyl)- acetamide Route 2, Step 1 SM:4-Fluoroaniline (Sigma Aldrich) Int-39

2-Chloro-N-pyridin-3-yl-acetamide Route 2 Step 1 SM: 3-Aminopyridine(Sigma Aldrich) Int-44

2-Chloromethyl-pyridin-1-ol Route 4, Step 1 SM: 2-Chloromethyl- pyridineHydrochloride (Sigma Aldrich) Int-45

2-Chloromethyl-6-methyl-pyridine Hydrochloride Route 4, Step 4 SM:6-Methyl-2- pyridinemethanol (Sigma Aldrich) Int-46

2-Chloromethyl-5-methyl-pyridine Hydrochloride Route 4, Steps 1-4 SM:2,5-Lutidine (Sigma Aldrich) Int-47

2-Chloromethyl-4-methyl-pyridine Hydrochloride Route 4, Steps 1-4 SM:2,4-Lutidine (Sigma Aldrich) Int-48

2-Chloromethyl-3-methyl-pyridine Hydrochloride Route 4, Steps 1-4 SM:2,3-Lutidine (Sigma Aldrich) Int-49

2-Chloromethyl-3,5-dimethyl- pyridine Hydrochloride Route 4, Steps 1-4SM: 2,3,5-Collidine (Sigma Aldrich) Int-50

2-Chloromethyl-6-fluoro-pyridine Hydrochloride Route 5, Step 3c SM:2-Fluoro-6- methylpyridine (Oakwood Product) Int-51

2-Chloromethyl-6-bromo-pyridine Hydrochloride Route 4, Step 4 SM:(6-Bromo-pyridin-2- yl)-methanol (Sigma Alrich) Int-52

2-Chloromethyl-5-ethyl-pyridine Route 4, Steps 1-4 SM: 5-Ethyl-2-methypyridine (Sigma Aldrich) Int-53

2-Chloromethyl-5-chloro-pyridine Route 1, Step 2; Route 4, Step 4 SM:5-Chloropyridine-2- carboxylic Acid (Matrix Scientific) Int-54

Methanesulfonic acid (S)-1- pyridin-2-yl-ethyl ester Route 1, Step 3 SM:(R)-alpha-Methyl-2- pyridinemethanol (Sigma Aldrich) Int-55

Methanesulfonic acid (R)-1- pyridin-2-yl-ethyl ester Route 1, Step 3 SM:(S)-alpha-Methyl-2- pyridinemethanol (Sigma Aldrich) Int-57

2-Bromomethyl-7-fluoro-quinoline Route 5, Step 3a SM: 7-Fluoro-2-methylquinoline (Sigma Aldrich) Int-58

2-Bromomethyl-6-fluoro-quinoline Route 5, Step 3a SM: 6-Fluoro-2-methylquinoline (Sigma Aldrich) Int-59

2-Chloromethyl-6-methyl- quinoline Route 4, Steps 1-4 SM:2,6-Dimethylquinoline (Sigma Aldrich) Int-60

2-Chloro-6-bromomethyl-quinoline Route 5, Steps 1-3a SM: Cinnamoylchloride (Sigma Aldrich) and p- toluidine (Sigma Aldrich) Int-71

5-Fluoro-2-(4-iodomethyl-phenyl)- thiazole Route 6, Step 1-2a; Route 1,Step 3b Int-72

Methanesulfonic acid 4-(5-methyl- thiazol-2-yl)-benzyl ester Route 6,Step 1-2b; Route 1, Step 3d Int-73

Methanesulfonic acid 4-(6- methoxy-pyridin-3-yl)-benzyl ester Route 6,Step 1; Route 1, Step 3d Int-74

4-(3-Bromomethyl-phenyl)-4- methoxy-tetrahydro-pyran Route 9, Step 1;Route 5, Step 3a Int-75

5-Bromo-2-chloromethyl-pyridine Route 4, Step 4 (5-Bromo-pyridin-2-yl)-methanol (Biofine International) Int-76

2-Bromo-5-iodomethyl-pyridine Route 1, Step 3b (6-Bromo-pyridin-3-yl)-methanol (Biofine International) Int-118

5-Bromo-pyrazin-2-ylamine Route 5, Step 3b SM: Aminopyrazine (Lancaster)Int-135

3-Phenoxy-benzoyl chloride Route 7, Step 1 SM: 3-Phenoxy-benzoic acid(Sigma Aldrich) Int-136

4-Phenoxy-benzoyl chloride Route 7, Step 1 SM: 4-Phenoxy-benzoic acid(Sigma Aldrich) Int-140

1-tert-Butylsulfanyl-4,4-dimethyl- pentan-2-one Route 10, Steps 1-2

Route 1: Step 1: BOC Protection (Int-10)

3-Azetidinecarboxylic acid (Sigma Aldrich, 0.25 g, 2.5 mmol) wasdissolved in tBuOH (5 mL) and 1N NaOH (2.7 mL, 2.7 mmol). Di-tert-butyldicarbonate (0.59 g, 2.7 mmol) was added, and the reaction was stirredovernight at room temperature. The reaction was diluted with water,acidified slowly to pH 4 with 1N HCl, and the mixture was extracted withEtOAc until all product was removed from the aqueous layer by ninhydrinstain. Tne combined organic layers were dried, filtered, andconcentrated to give the desired product.

Step 2: Borane Reduction (Int-10)

Acid from Step 1 (0.7 g, 3.5 mmol) was dissolved in THF and cooled to 0°C. under N₂. Borane-THF complex was added to the solution, and thereaction was stirred at room temperature overnight. The reaction wascooled to 0° C. and quenched with water. The mixture was extracted 3times with EtOAc, the combined organic layers were dried over MgSO₄,filtered, and concentrated. The crude material was filtered through aplug of silica gel and eluted with EtOAc to give the desired compound.

Step 3a: Br₂ Bromide Formation (Int-10)

Triphenylphosphine (1.7 g, 6.5 mmol) was dissolved in DMF and cooled to0° C. Bromine (0.31 mL, 5.9 mmol) as added slowly, and the solution wasstirred for 30 minutes. Alcohol from Step 2 (0.32 g, 2.0 mmol) was addedin DMF and the reaction was stirred at room temperature overnight. Themixture was diluted with water, extracted 3 times with EtOAc, and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. The crude material was filtered through a plug of silicagel and eluted with EtOAc to give the desired compound.

Step 3b: I₂ Iodide Formation (Int-73)

(6-Bromo-pyridin-3-yl)-methanol (0.5 g, 2.7 mmol) was dissolved intoluene (20 mL). Triphenylphosphine (0.9 g, 3.5 mmol) and imidazole (0.4g, 6.0 mmol) were added, followed by a solution of iodine (0.88 g, 3.5mmol) in toluene dropwise. The reaction was stirred at room temperaturefor 15 minutes, and then poured into saturated aq. Na₂CO₃. The organiclayer was washed with aq. sodium thiosulfate, water, then dried overMgSO₄, filtered, and concentrated. The crude material was purified onsilica gel (EtOAc:hexanes gradient) to give the desired product.

Step 3c: Tosylation (Int-21)

(S)-(−)-1-(tert-Butoxycarbonyl)-2-pyrrolidinemethanol (1.0 g, 5.0 mmol)was dissolved in pyridine (3 mL), and toluenesulfonyl chloride (1.0 g,5.5 mmol) was added. The reaction was stirred overnight at roomtemperature, and diluted with water and extracted with EtOAc. Thecombined organic layers were washed with water, dried over MgSO₄,filtered, and concentrated. The residue was purified on silica gel (0 to10% EtOAc in hexanes) to give the desired product.

Step 3d: Mesylation (Int-55)

(R)-alpha-Methyl-2-pyridinemethanol (1.0 g, 8.1 mmol) was dissolved inCH₂Cl₂ (20 mL) and cooled to 0° C. Triethylamine (1.7 mL, 12.2 mmol) wasadded, followed by methanesulfonyl chloride (0.66 mL, 8.4 mmol)dropwise. The reaction was stirred for 30 minutes, and then diluted withCH₂Cl₂, washed with water, dried over MgSO₄, filtered, and concentratedto obtain the desired product.

Route 2: Step 1: Amide Formation (Int-19)

Cyclopropylamine (0.35 mL, 5.0 mmol) and triethylamine (0.7 mL, 5.1mmol) were dissolved in CH₂Cl₂ (10 mL). The reaction was cooled to −10°C. and chloroacetyl chloride (0.4 mL, 5.0 mmol) was added dropwise. Thereaction was stirred at −10° C. for 1 hour, then at room temperature for2 hours, followed by a quench with water. The aqueous layer wasextracted with CR₂Cl₂, and the organic layers were dried, filtered, andconcentrated to give the desired product.

Route 3: Step 1: Imine Formation (Int-20)

Chloroacetonitrile (0.5 g, 6.6 mmol) was dissolved in Et₂O (10 mL) andcooled to 0° C. EtOH (0.43 mL, 7.3 mmol) was added, followed by 4N HClin 1,4-dioxane (15 mL, 59.6 mmol). The reaction was stirred at 0° C. for4 days, and then concentrated to give the desired product as a whitesolid.

Step 2: Cyclization (Int-20)

Imine from Step 1 (0.3 g, 2.0 mmol) was dissolved in EtOH (4 mL) andcooled to 0° C. 1,3-Diaminopropane (0.17 mL, 2.0 mmol) was added,followed by iPr₂NEt (0.35 mL, 2.0 mmol). The reaction was stirred at 0°C. for 2 hours, and then 4N HCl in 1,4-dioxane (0.5 mL, 2 mmol) wasadded. The mixture was filtered, and the filtrate was concentrated togive the desired product.

Route 4:

Step 1: mCPBA Oxidation (Int-46)

2,5-Lutidine (5.0 g, 46.7 mmol) was dissolved in CHCl₃ (125 mL) andcooled to 0° C. m-Chloroperoxybenzoic acid (70%, 13.9 g, 55.2 mmol) wasadded, and the reaction was stirred overnight at room temperature. Themixture was washed with saturated aq. Na₂CO₃, dried over Na₂SO₄,filtered, and concentrated to give the desired product.

Step 2: Acetylation (Int-46)

The N-oxide from Step 1 (46.7 mmol) was dissolved in acetic anhydride(25 mL) and heated to reflux at 100° C. for one hour. The mixture wascooled to room temperature, and ethanol (46.7 mmol) was slowly added toquench the reaction. The solution was evaporated to dryness and purifiedon silica gel to give the desired product.

Step 3: Hydrolysis (Int-46)

Acetate from Step 2 (46.7 mmol) was dissolved in concentrated HCl (20mL) and refluxed for 1 hour. The reaction was cooled and evaporated todryness to give an orange solid, which was used directly in the nextreaction.

Step 4: SOCl₂ Chloride Formation (Int-46)

Alcohol from Step 3 (1.0 g, 8.1 mmol) was dissolved in thionyl chloride(3 mL) and stirred at room temperature for 30 minutes under N₂. Themixture was evaporated to dryness to give the desired product as ahydrochloride salt, which was used directly in subsequent reactions.

Route 5: Step 1: Condensation (Int-60)

p-Toluidine (10 g, 60.0 mmol) and triethylamine (8.4 mL, 60.3 mmol) weredissolved in CH₂Cl₂ (200 mL) at room temperature. Cinnamoyl chloride(6.5 g, 60.7 mmol) was added, and the reaction was stirred for 1 hour.The reaction was washed with water, dried, filtered, and concentrated.To the residue was added aluminum chloride (5 g, 37.5 mmol), which washeated neat. After 45 minutes, ice was added to form a precipitate. Themixture was stirred overnight at room temperature. The precipitate wasthen filtered and dissolved in CH₂Cl₂, washed with 1N HCl, brine, driedover MgSO₄, filtered, and concentrated. The residue was recrystallizedfrom ethanol to give the desired quinolinone product.

Step 2: POCl₃ Chloride Formation (ant-60)

Quinolinone from Step 1 (3.12 g, 19.6 mmol) was heated to 90° C. inPOCl₃ (10 mL). Once no starting material remained, the reaction wascooled and concentrated. The residue was diluted with EtOAc andsaturated aq. NaHCO₃, and the aqueous layer was extracted with EtOAc.The combined organics were dried, filtered, and concentrated to give thechloroquinoline product.

Step 3a: NBS Bromide Formation (Alkyl) (ant-60)

Quinoline from Step 2 (19.6 mmol) was heated to 80° C. for 1 hour inbenzene (200 mL) with NBS (3.6 g, 20.2 mmol) and catalytic benzoylperoxide. The reaction mixture was concentrated and purified on silicagel to give the desired product.

Step 3b: NBS Bromide Formation (Aryl) (Int-118)

2-Aminopyrazine (4 g, 42 mmol) was dissolved in water (2 mL) and DMSO(70 mL), and NBS (7.5 g, 42 mmol) was added over 1 hour at 0° C. Thereaction was warmed to room temperature and stirred overnight. Themixture was poured onto ice and extracted 4 times with EtOAc. Thecombined organic layers were washed with 5% Na₂CO₃, water, and brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedon silica gel to give the desired product.

Step 3c: NCS Chloride Formation (Int-50)

2-Fluoro-6-methylpyridine (1.11 g, 10 mmol), NCS (2.0 g, 15 mmol), andcatalytic benzoyl peroxide were dissolved in benzene and heated toreflux overnight. The reaction was concentrated and diluted with waterand EtOAc. The organic layer was washed with saturated aq. NaHCO₃,dried, filtered, and concentrated. The residue was purified on silicagel to give the desired product.

Route 6: Step 1: Suzuki Coupling (Int-71)

To (4-Hydroxymethylphenyl)boronic acid (Combi-Blocks; 1.0 g, 6.6 mmol)in DME/H₂O (16 mL, 2:1) was added 2-bromothiazole (1.2 g, 7.2 mmol) andK₂CO₃ (2.7 g, 19.7 mmol). The reaction was degassed with N₂ for 20minutes. Pd(PPh₃)₄ (0.76 g, 0.7 mmol) was added and the reaction wasfurther degassed for 10 minutes. The reaction was then heated to 90° C.overnight under N₂. LCMS confirmed the formation of the product. Thereaction was partitioned between water and EtOAc and the aqueous layerwas extracted twice with EtOAc. The combined organic layers were driedover MgSO₄, filtered, concentrated, and purified on silica gel(EtOAc:hexanes gradient) to give the desired product.

Step 2a: F-Alkylation (Int-71)

Thiazole from Step 1 (0.35 g, 1.8 mmol) was dissolved in THF (15 mL) andcooled to −78° C. under N₂. n-Butyllithium (1.6M; 4.6 mL, 7.3 mmol) wasadded dropwise, followed by NFSi (1.2 g, 3.7 mmol). The reaction wasquenched at −78° C. with saturated aq. NH₄Cl, and diluted with EtOAc andwater. The aqueous layer was extracted twice with EtOAc, and thecombined organics were dried over MgSO₄, filtered, and concentrated. Theresidue was purified on silica gel to give the desired compound.

Step 2b: Me-Alkylation (Int-72)

Thiazole from Step 1 (0.33 g, 1.7 mmol) was dissolved in THF (15 mL) andcooled to −78° C. under N₂. n-Butyllithium (1.6M; 4.3 mL, 6.7 mmol) wasadded dropwise, followed by iodomethane (0.16, 2.6 mmol). The reactionwas quenched at −78° C. with saturated aq. NH₄Cl, and diluted with EtOAcand water. The aqueous layer was extracted twice with EtOAc, and thecombined organics were dried over MgSO₄, filtered, and concentrated. Theresidue was purified on silica gel to give the desired compound.

Route 7: Step 1: Acid Chloride Formation (Int 135)

3-Phenoxy-benzoic acid (0.50 g, 0.23 mmol) was dissolved in CH₂Cl₂.Oxalyl chloride (0.32 g, 0.25 mmol) was added, followed by 1-2 drops ofDMF. The reaction was stirred at room temperature, and then concentratedto give the desired acid chloride.

Route 8: Step 1: Alkylation (Int-5)

To imidazole (0.41 g, 6.0 mmol) in CH₂Cl₂ was added bromoacetonitrile(0.21 g, 2.0 mmol), and the reaction was refluxed for 30 minutes. Themixture was cooled to room temperature and filtered, and the filtratewas concentrated to give the desired product.

Route 9: Step 1: Methylation (Int-74)

To 4-m-Tolyl-tetrahydro-pyran-4-ol (2.5 g, 13.0 mmol) in THF (50 mL) wasadded sodium hydride (60%; 0.8 g, 20.0 mmol) at room temperature.Iodomethane (1.25 mL, 20 mmol) was added, and the reaction was stirredfor 1 hour. The mixture was quenched with water, and the aqueous layerwas extracted with EtOAc. The combined organic layers were washed withwater, dried over MgSO₄, filtered, and concentrated. The residue waspurified on silica gel to give the desired compound.

Route 10: Step 1: Bromination

To 4,4-Dimethyl-pentan-2-one (3.7 mL, 26.3 mmol) in MeOH (2.8 mL) at 0°C. was added bromine (1.34 mL, 26.3 mmol) in a single stream. Thereaction was warmed slowly to 10° C. for 30 minutes to initiate thereaction, and then stirred at room temperature for an additional 15minutes. The reaction was diluted with water and diethyl ether, and theaqueous layer was extracted with diethyl ether three times. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated to givethe desired product as a colourless liquid.

Step 2: Thiol Addition

Bromide from Step 1 (26.3 mmol) was dissolved in THF (50 mL), and themixture was cooled to 0° C. 2-Methyl-2-propanethiol (2.45 mL, 21.6 mmol)was added, followed by triethylamine (7.9 mL, 56.8 mmol). The reactionwas stirred at room temperature for 18 hours, then diluted with water.The aqueous layer was extracted with diethyl ether, and the combinedorganic layers were dried over MgSO4, filtered, and concentrated to givethe desired product.

Example 13-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid Step 1: N-[4-(Pyridin-2-ylmethoxy)-phenyl]-acetamide

A mixture of 4-acetanidophenol (Sigma-Aldrich; 73.6 g),2-chloromethylpyridine hydrochloride (80 g) and cesium carbonate (320 g)in DMF (IL) was stirred at 70° C. for 2 days. The mixture was cooled,poured into water (2 L) and extracted with EtOAC (×6). The organiclayers were washed with brine, dried (MgSO₄) and filtered to give a tansolid (A-1, 114 g) which was used as such in the next step.

Step 2: 4-(Pyridin-2-ylmethoxy)-phenylamine hydrochloride

A-1 (114 g) was dissolved in EtOH (1 L) and to this was added KOH (50 g)in water (200 mL). The solution was heated to 110° C. for 2 days, KOH(20 g in 100 mL water) was added and heating continued for a further 2days. The solution was cooled, the EtOH was removed in vacuo and theresidue partitioned between EtOAc and water. After extraction of thewater with EtOAc (×3), the organic layers were washed with brine, dried(MgSO₄) and filtered. To this solution was added saturated HCl in EtOAcand a precipitated formed immediately. Collection of the solids byfiltration followed by drying under vacuum provided the title compound(A-2, 95 g) as a pink solid.

Step 3: [4-Pyridin-2-ylmethoxy)-phenyl]-hydrazine dihydrochloride

A-2 (95 g) was dissolved in water (1 L) at 0° C. and to this was addedNaNO₂ (26 g) in water (100 mL). The diazonium salt was allowed to formover 45 minutes and then it was poured slowly over 15 minutes into arapidly stirred mixture of Na₂S₂O₄ (350 g) in water (1 L) and ether (1L) at 0° C. Stirring continued for 40 minutes then mixture was madebasic using conc. KOH. After extraction using EtOAc (×2) the organiclayers were washed with water, then brine, dried (MgSO₄) and filtered.To this solution was added saturated HCl in EtOAc and a precipitatedformed immediately. Collection of the solids by filtration followed bydrying under vacuum provided the title compound as a tan solid (A-3, 75g).

Step 4:3-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester

A-3 (75 g), ethyl 5-(t-butylthio)-2,2-dimethyl-4-oxo-pentanoate(prepared according to the procedures described in U.S. Pat. No.5,288,743 issued Feb. 22, 1994; 64 g), NaOAc (40 g) in toluene (800 mL)and HOAc (400 mL) was stirred at room temperature for 3 days. Themixture was poured into water and made basic with solid Na₂CO₃. Themixture was extracted with EtOAc (×3), then washed with water (×2),brine, dried (MgSO₄), filtered and concentrated to give a dark red-blackoil. Column chromatography of the mother liquor (silica gel packed inhexanes; eluting with hexane then hexane-EtOAc 9:1 rising to 4:1)afforded 68 g of the title compound (A4), as a yellow solid.

Step 5:3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester

3-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester (A-4; 20.0 g, 45.4 mmol) was dissolved in DMF (150 mL)and cooled to −10° C. under N₂. Sodium hydride (60% dispersion inmineral oil; 2.0 g, 50.0 mmol) was added portionwise, and the reactionwas stirred at −10° C. for 45 minutes until the foam had disappeared. Tothis dark brown-reddish solution was added methanesulfonic acid4-(6-methoxy-pyridin-3-yl)-benzyl ester (Int-72; 16.0 g, 54.5 mmol) inDMF dropwise. The reaction was then stirred at −10° C. for 1 hour andallowed to warm to room temperature slowly. After 16 hours, LCMSconfirmed the formation of the product. The reaction was quenched withsaturated NH₄Cl and diluted with methyl tert-butyl ether (MTBE) andwater. The aqueous phase was extracted twice with MTBE. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated, andthe crude product was purified by column chromatography to give thedesired product (A-5).

Step 6:3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid

A-5 (21.5 g, 33.7 mmol) was dissolved in THF (100 mL) and MeOH (100 mL)and stirred until it became a clear solution. 3N LiOH aqueous solution(56 mL, 168.5 mmol) was added and the reaction was refluxed at 80° C.for 2 hours. LCMS confirmed the formation of the product, so thereaction was cooled to room temperature and partitioned between EtOAcand water. The pH of the aqueous solution was adjusted to pH 1 with 10%HCl, and the aqueous phase was extracted three times with EtOAc. Thecombined organic layers were washed with water, dried over MgSO₄,filtered, and concentrated to give the desired free acid (A-6).

Example 2 Preparation of Compound 3-1, Compound 3-2, and Compound 3-3

Compound 3-1, Compound 3-2, and Compound 3-3 were prepared as outlinedin Scheme B. A detailed illustrative example of the reaction conditionsshown in Scheme B is described for the synthesis of1-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2-methyl-propan-2-ol.

Step 1: 4-tert-Butylsulfanyl-3-oxo-butyric acid ethyl ester

Ethyl 4-chloroacetoacetate (7.5 mL, 51.9 mmol), 2-methyl-2-propanethiol(5.6 mL, 49.7 mmol), triethylamine (10.8 mL, 77.4 mmol), and catalytictetrabutylammonium bromide were dissolved in THF (250 mL) and stirred atroom temperature overnight. Silica gel was added, and the mixture wasconcentrated and filtered over a plug of silica gel to obtain thedesired product (B-1), which was used without further purification.

Step 2: (3-tert-Butylsulfanyl-5-methoxy-1H-indol-2-yl)-acetic acid ethylester

4-Methoxyphenylhydrazine hydrochloride (7.7 g, 44.1 mmol) and B-1 (7.4g, 33.9 mmol) were dissolved in 2-propanol (150 mL) and heated to refluxfor 24 hours. The reaction mixture was concentrated and partitionedbetween EtOAc and saturated aq. NaHCO₃. The aqueous layer was extractedwith EtOAc, and the combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedon silica gel (0 to 30% EtOAc in hexanes) to give the desired product(B-2).

Step 3: (3-tert-Butylsulfanyl-5-hydroxy-1H-indol-2-yl)-acetic acid ethylester

Aluminum chloride (7.5 g 56.0 mmol) was suspended in tert-butylthiol (21mL, 186.7 mmol) at 0° C. B-2 (6.0 g, 18.7 mmol) was added in CH₂Cl₂ (21mL), and the reaction was allowed to warm to room temperature. After 2hours, the reaction was complete by TLC analysis, so the solution pouredinto ice and acidified with 10% HCl aqueous solution. The aqueous layerwas extracted three times with EtOAc, the combined organics were driedover MgSO₄, filtered, and concentrated to give the desired product(B-3).

Step 4: 3-tert-Butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-ol

B-3 (2.2 g, 7.0 mmol) was dissolved in THF (70 mL) and cooled to 0° C.Methylmagnesium chloride (3M; 14 mL, 42.0 mmol) was added dropwise, andthe reaction was stirred for 1 hour at room temperature. The reactionwas quenched with aq. NH₄Cl and extracted with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered, concentrated, andpurified on silica gel to give the desired product (B-4).

Step 5:1-[3-tert-Butylsulfanyl-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2-methyl-propan-2-ol

To B-4 (0.18 g, 0.61 mmol) in DMF (6 mL) was added cesium carbonate(11.0 g, 3.1 mmol). The reaction was stirred at room temperature for 30minutes, and then 2-chloromethylpyridine hydrochloride (0.11 g, 0.67mmol) and tetrabutylammonium iodide (0.05 g, 0.13 mmol) were added, andthe reaction was stirred at room temperature for an additional 16 hours.The reaction was partitioned between water and diethyl ether, and theaqueous layer was extracted with diethyl ether. The combined organiclayers were washed with water, dried over MgSO₄, filtered, andconcentrated. The residue was purified on silica gel to give the desiredproduct (B-5).

Step 6:1-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2-methyl-propan-2-ol

To B-5 (0.05 g, 0.13 mmol) in DMF (3 mL) was added cesium carbonate(0.21 g, 0.65 mmol). The reaction was stirred at room temperature for 30minutes, and then 1-chloro-4-chloromethylbenzene (0.03 g, 0.20 mmol) andtetrabutylammonium iodide (0.05 g, 0.13 mmol) were added, and thereaction was stirred at room temperature overnight. The reaction waspartitioned between water and EtOAc, and the aqueous layer was extractedwith EtOAc. The combined organics were washed with water, dried overMgSO₄, filtered, concentrated, and purified on silica gel (EtOAc:hexanesgradient) to give the desired compound (B-6).

Mass spectrometry data of Compound 3-1, Compound 3-2, and Compound 3-3,is shown in Tables 1-3.

Example 3 Preparation of Compound 1-1, Compound 1-3, Compound 1-4,Compound 1-5, Compound 1-11, Compound 1-12, Compound 1-13, Compound1-14, Compound 1-22, Compound 1-59, Compound 1-60, Compound 1-63, andCompound 3-6

Compound 1-1, Compound 1-3, Compound 1-4, Compound 1-5, Compound 1-11,Compound 1-12, Compound 1-13, Compound 1-14, Compound 1-22, Compound1-59, Compound 1-60, Compound 1-63, and Compound 3-6 were prepared asoutlined in Scheme C. A detailed illustrative example of the reactionconditions shown in Scheme, C is described for the synthesis of(S)-2-[3-tert-]Butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (Compound 1-1).

Step 1: N-(4-Chloro-benzyl)-N-(4-methoxy-phenyl)-hydrazine Hydrochloride

A solution of 4-Methoxyphenylhydrazine hydrochloride (10.0 g, 57.3mmol), 4-chlorobenzylchloride (9.2 g, 57.2 mmol), tetrabutylammoniumbromide (30.7 g, 11.5 mmol), and diisopropylethylamine (20 mL, 115 mmol)in CH₂Cl₂ (250 mL) was stirred at room temperature for several days. Thereaction mixture was diluted with water and the organic layer was driedover MgSO₄, filtered, and concentrated. The residue was taken up intoluene (200 mL) and diethyl ether (100 mL), and 1 equivalent of 4N HClin dioxane was added at 0° C. The mixture was stirred at roomtemperature for 2 hours, and then evaporated to dryness to give thedesired product (C-1; X=Cl) as a purple solid.

Step 2:3-[1-(4-Chloro-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester

C-1 (˜16 g, 57.3 mmol), ethyl5-(t-butylthio)-2,2-dimethyl-4-oxo-pentanoate (prepared according to theprocedures described in U.S. Pat. No. 5,288,743 issued Feb. 22, 1994;14.8 g, 57.3 mmol), NaOAc (5.2 g) in toluene (120 mL) and HOAc (66 mL)was stirred at room temperature in the dark for 5 days. The mixture waspartitioned between EtOAc and water, and the organic layer was stirredwith solid NaHCO₃, filtered, and evaporated. The residue was purified onsilica gel (0 to 55% CH₂Cl₂ in hexanes), and the isolated product wasrecrystallized from hexanes to give the desired product (C-2; X=Cl).

Step 3:3-[1-(4-Chloro-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester

Aluminum chloride (0.820 g 6.15 mmol) was suspended in tert-butylthiol(1.8 mL, 16 mmol) and cooled to 0° C. C-2 (1.0 g, 2.0 mmol) was added inCH₂Cl₂ (2.4 mL), and the reaction was allowed to warm to roomtemperature. After 3 hours, the reaction was complete by TLC analysis,so the solution was diluted with CH₂Cl₂ and washed with 10% ice-cooledHCl aqueous solution. The aqueous layer was extracted three times withCH₂Cl₂, the combined organics were dried over MgSO₄, filtered, andconcentrated to give the desired product (C-3; X=Cl) as a colourlessfoam.

Step 4:(S)-2-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-2-(2-ethoxycarbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

To3-[1-(4-Chloro-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester (C-3; 0.5 g, 1.05 mmol) in DMF (2.5 mL) was addedN—BOC—(S)-2-(toluene-4-sulfonyloxymethyl)pyrrolidine (0.39 g, 1.10mmol), and Cs₂CO₃ (0.69 g, 2.1 mmol). The reaction was stirred at 45° C.for 2 hours, and then catalytic potassium iodide was added and thereaction was heated to 60° C. overnight. The reaction mixture wasdiluted with EtOAc, washed with water, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified on silica get (0 to 15% EtOAc inhexanes) to give the desired product (C-4; X=Cl).

Step 5:(S)-2-[3-tert-Butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1-indol-5-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The ester from Step 4 (0.16 g, 0.26 mmol) was dissolved in MeOH (1 mL),THF (1 mL), and water (1 mL). Lithium hydroxide (0.6 g, 1.43 mmol) wasadded, and the reaction was heated for 12 hours until no startingmaterial was seen by TLC analysis. The reaction was diluted with water,acidified to pH 5 with citric acid, and extracted with EtOAc. Thecombined organic layers were washed with water, dried over MgSO₄,filtered, and concentrated. The residue was purified on silica gel (0 to40% EtOAc in hexanes) to give the desired product (C-5; X=Cl).

Mass spectrometry data for Compound 1-1, Compound 1-3, Compound 14,Compound 1-5, Compound 1-11, Compound 1-12, Compound 1-13, Compound1-14, Compound 1-22, Compound 1-59, Compound 1-60, Compound 1-63, andCompound 3-6, is shown in Tables 1-3.

Notes:

For Compound 1-11, after Step 4, the dihydroimidazolyl in the precursorwas reacted with di-tert-butyl dicarbonate to give theBOC-dihydroimidazolyl in the final product.

For Compound 3-6, i) after Step 4, the ketone in the precursor wasreduced with diisobutylaluminum hydride to give the alcohol in the finalproduct, ii) Step 5 was not performed.

Example 43-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid Step 1:3-{3-tert-Butylsulfanyl-5-hydroxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

The phenol from Example 3, Step 3 (C-3, X=Br; 35.0 g, 67.5 mmol),bis(pinacolato)diboron (Combi-Blocks; 25.0 g, 98.4 mmol), and KOAc (19.9g, 209.1 mmol) was dissolved in 1,4-dioxane (350 mL) and degassed withN₂ for 30 minutes. PdCl₂dppf (2.5 g, 3.1 mmol) was added, and thereaction mixture was degassed an additional 30 minutes with N₂. Thereaction was heated at 85° C. overnight. The reaction mixture waspartitioned between water and EtOAc, the aqueous layer was extractedthree times with EtOAc, the combined organic layers were washed withwater, brine, dried over MgSO₄, filtered, and concentrated. The crudematerial was purified on silica gel (15% EtOAc in hexanes) to give thedesired product (D-1, 33.5 g).

Step 2:3-{3-tert-Butylsulfanyl-5-hydroxy-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

D-1 (25.34 g, 44.8 mmol), 5-bromo-2-methoxypyridine (Combi-blocks; 10.9g, 70.3 mmol), and K₂CO₃ (15.5 g, 112.1 mmol) were dissolved in DME (300mL) and water (150 mL) and degassed with N₂ for 30 minutes. Pd(PPh₃)₄(1.6 g, 1.4 mmol) was added, and the reaction mixture was degassed withN₂ for an additional 15 minutes. The solution was heated to 80° C.overnight, and then cooled to room temperature and diluted with EtOAcand water. The aqueous layer was extracted 3 times with EtOAc, thecombined organic layers were washed with water, brine, dried over MgSO₄,filtered, and concentrated. The crude material was purified on silicagel (0 to 8% EtOAc in hexanes) to give the desired product (D-2, 23.7g).

Step 3:3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

To3-{3-tert-Butylsulfanyl-5-hydroxy-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester (D-2; 6.5 g, 11.9 mmol) in MeCN (75 mL) was added2-bromomethyl-6-fluoro-quinoline (3.14 g, 13.1 mmol), and Cs₂CO₃ (9.7 g,29.8 mmol). The reaction was stirred at room temperature overnight,after which LCMS showed the reaction was complete. The reaction mixturewas partitioned between EtOAc and water, the aqueous layer was extractedwith EtOAc, and the combined organic layers were dried over MgSO₄,filtered, and concentrated. The residue was purified on silica gel (0 to25% EtOAc in hexanes) to give the desired product (D-3, 7.6 g).

Step 4:3-{3-ter-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid

D-3 (6.58 g, 9.3 mmol) was dissolved in MeOH (36 mL), THF (75 mL), andwater (36 mL). Lithium hydroxide (2.42 g, 57.7 mmol) was added, and thereaction was heated at 60° C. for 6 hours until no starting material wasseen by TLC analysis. The reaction was diluted with water, acidified topH 5 with citric acid, and extracted with EtOAc. The combined organiclayers were washed with water, dried over MgSO₄, filtered, andconcentrated. The residue was triturated with hexane:EtOAc (9:1)overnight, and filtered to give the desired product (D-4, 5.9 g).

Example 5 Preparation of Compound 2-10

Compound 2-10 was prepared as shown in Scheme E. A detailed illustrativeexample of the reaction conditions shown in Scheme E is described forthe synthesis of3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid.

Step 1:3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester

To3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester (C-3; 0.25 g, 0.48 mmol) in DMF (2 mL) was added2-chloromethyl-5-methyl-pyridine hydrochloride (0.13 g, 0.72 mmol),Cs₂CO₃ (0.39 g, 1.21 mmol), and catalytic tetrabutylammonium iodide. Thereaction was stirred at room temperature overnight, after which LCMSshowed the reaction was complete. The reaction mixture was partitionedbetween EtOAc and water, the aqueous layer was extracted with EtOAc, andthe combined organic layers were dried over MgSO₄, filtered, andconcentrated. The crude material was purified on silica gel (0 to 15%EtOAc in hexanes) to give an additional the desired product (E-1, 0.30g).

Step 2:3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

E-1 (0.06 g, 0.10 mmol), 2-methoxy-pyridine-5-boronic acid (0.02 g, 0.14mmol), and K₂CO₃ (0.03 g, 0.24 mmol) were dissolved in DME (1 mL) andwater (0.5 mL) and degassed with N₂ for 10 minutes. Pd(PPh₃)₄ (0.01 g,0.01 mmol) was added, and the reaction mixture was degassed with N₂ foran additional 10 minutes. The solution was heated to 80° C. for 4 hours,and then cooled to room temperature and diluted with EtOAc and water.The aqueous layer was extracted 3 times with EtOAc, the combined organiclayers were washed with water, brine, dried over MgSO₄, filtered, andconcentrated. The crude material was purified on silica gel (0 to 50%EtOAc in hexanes) to give the desired product (E-2).

Step 3:3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid

E-2 (0.22 g, 0.31 mmol) was dissolved in MeOH (0.1 mL), THF (0.1 mL),and water (0.1 mL). Lithium hydroxide, 1N aqueous solution (0.11 mL) wasadded, and the reaction was heated at 60° C. for 4 hours until nostarting material was seen by LCMS. The reaction was diluted with waterand EtOAc, acidified to pH 5 with citric acid, and extracted with EtOAc.The combined organic layers were washed with water, dried over MgSO₄,filtered, and concentrated to give the desired product (F-4).

Mass spectrometry data for Compound 2-10 is shown in Tables 1-3.

Example 6 Preparation of Compound 2-1

Compound 2-1 was prepared as shown in Scheme F. A detailed illustrativeexample of the reaction conditions shown in Scheme F is described forthe synthesis of3-{3-tert-butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid.

Step 1:3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester

To3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester (C-3; 2.0 g, 3.9 mmol) in MeCN (25 mL) was added2-bromomethyl-6-fluoro-quinoline (1.0 g, 4.2 mmol), and Cs₂CO₃ (2.5 g,7.7 mmol). The reaction was stirred at room temperature overnight, afterwhich LCMS showed the reaction was complete. The reaction mixture waspartitioned between EtOAc and water, the aqueous layer was extractedwith EtOAc, and the combined organic layers were dried over MgSO₄,filtered, and concentrated. The residue was recrystallized inEtOAc:hexane to give the desired product (F-1, 1.9 g). The filtrate wasconcentrated and purified on silica gel (0 to 15% EtOAc in hexanes) togive an additional 1 g of F-1.

Step 2:3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

F-1 (1.0 g, 1.5 mmol), bis(pinacolato)diboron (Combi-Blocks; 1.1 g, 4.3mmol), and KOAc (0.44 g, 4.5 mmol) was dissolved in 1,4-dioxane (15 mL)and degassed with N₂ for 10 minutes in a sealed vessel. PdCl₂dppf (0.13g, 0.16 mmol) was added, and the reaction mixture was degassed anadditional 10 minutes with N₂. The vessel was sealed and the reactionwas heated at 95° C. overnight. The reaction mixture was partitionedbetween water and EtOAc, the aqueous layer was extracted three timeswith EtOAc, the combined organic layers were washed with water, brine,dried over MgSO₄, filtered, and concentrated. The crude material waspurified on silica gel (0 to 20% EtOAc in hexanes) to give the desiredproduct (F-2).

Step 3:3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-[4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

F-2 (0.25 g, 0.35 mmol), 2-bromo-6-methoxypyridine (0.09 g, 0.48 mmol),and K₂CO₃ (0.15 g, 1.05 mmol) were dissolved in DME (3.5 mL) and water(1.8 mL) and degassed with N₂ for 10 minutes. Pd(PPh₃)₄ (0.06 g, 0.05mmol) was added, and the reaction mixture was degassed with N₂ for anadditional 10 minutes. The solution was heated to 85° C. for 4 hours,and then cooled to room temperature and diluted with EtOAc and water.The aqueous layer was extracted 3 times with EtOAc, the combined organiclayers were washed with water, brine, dried over MgSO₄, filtered, andconcentrated. The crude material was purified on silica gel (0 to 25%EtOAc in hexanes) to give the desired product (F-3).

Step 4:3-{3-tert-Butylsulfanyl-5-(6-fluoro-quinolin-2-ylmethoxy)-1-(4-(6-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid

F-3 (0.22 g, 0.31 mmol) was dissolved in MeOH (1.5 mL), THF (3 mL), andwater (1.5 mL). Lithium hydroxide (0.08 g, 1.9 mmol) was added, and thereaction was heated at 60° C. for 3.5 hours until no starting materialwas seen by TLC analysis. The reaction was diluted with water, acidifiedto pH 5 with citric acid, and extracted with EtOAc. The combined organiclayers were washed with water, dried over MgSO₄, filtered, andconcentrated to give the desired product (F-4).

Mass spectrometry data for Compound 2-1 is shown in Tables 1-3.

Example 6 Preparation of Compound 1-2, Compound 1-6, Compound 1-7,Compound 1-8, Compound 1-9, Compound 1-10, Compound 1-15, Compound 1-16,Compound 1-17, Compound 1-18, Compound 1-19, Compound 1-20, Compound1-21, Compound 1-23, Compound 1-24, Compound 1-25, Compound 1-42,Compound 1-43, Compound 1-44, Compound 1-45, Compound 1-46, Compound1-47, Compound 1-48, Compound 1-49, Compound 1-50, Compound 1-51,Compound 1-52, Compound 1-53, Compound 1-54, Compound 1-55, Compound1-56, Compound 1-57, Compound 1-58, Compound 1-61, Compound 1-62,Compound 2-2, Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6,Compound 2-7, Compound 2-8, Compound 2-9, Compound 2-11, Compound 3-4,and Compound 3-5.

Compound 1-2, Compound 1-6, Compound 1-7, Compound 1-8, Compound 1-9,Compound 1-10, Compound 1-15, Compound 1-16, Compound 1-17, Compound1-18, Compound 1-19, Compound 1-20, Compound 1-21, Compound 1-23,Compound 1-24, Compound 1-25, Compound 142, Compound 1-43, Compound1-44, Compound 1-45, Compound 1-46, Compound 1-47, Compound 1-48,Compound 1-49, Compound 1-50, Compound 1-51, Compound 1-52, Compound1-53, Compound 1-54, Compound 1-55, Compound 1-56, Compound 1-57,Compound 1-58, Compound 1-61, Compound 1-62, Compound 2-2, Compound 2-3,Compound 24, Compound 2-5, Compound 2-6, Compound 2-7, Compound 2-8,Compound 2-9, Compound 2-11, Compound 34, and Compound 3-5 were preparedas shown in Scheme G. A detailed illustrative example of the reactionconditions shown in Scheme G is described for the synthesis of3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid (Compound 2-5).

Step 1:3-{3-tert-Butylsulfanyl-5-[(S)-1-(2,3-dihydro-1H-indol-2-yl)methoxy]-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester(S)-2-{3-tert-Butylsulfanyl-2-(2-ethoxycarbonyl-2-methyl-propyl)-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-5-yloxymethyl}-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester (0.23 g, 0.30 mmol) was dissolved in CH₂Cl₂ (1.5mL). TFA (1.5 mL) was added and the reaction was stirred at roomtemperature for 10 minutes until no starting material was seen by TLCanalysis. The solution was concentrated in vacuo, and the crude product(G-1) was used without further purification Step 2:3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

G-1 (0.30 mmol) was dissolved in CH₂C₂ (1 mL). Diisopropylethylamine(0.5 mL) was added, followed by acetic anhydride (33 uL, 0.35 mmol), andthe reaction was stirred at room temperature until no starting materialwas seen by LCMS. The reaction was diluted with CH₂Cl₂ and MeOH,concentrated, redissolved in CH₂Cl₂ and washed with water, dried overNa₂SO₄, filtered, and concentrated. The residue was purified on silicagel to give the desired product (C-2).

Step 3:3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid

G-2 (0.05 g, 0.07 mmol) was dissolved in MeOH (0.5 mL), THF (0.5 mL),and water (0.5 mL). Lithium hydroxide (0.03 g, 0.7 mmol) was added, andthe reaction was heated at 60° C. for 6 hours until no starting materialwas seen by TLC analysis. The reaction was diluted with water, acidifiedto pH 5 with citric acid, and extracted with EtOAc. The combined organiclayers were washed with water, dried over MgSO₄, filtered, andconcentrated. The residue was purified on silica gel to give the desiredproduct (G-3).

Mass spectrometry data for Compound 1-2, Compound 1-6, Compound 1-7,Compound 1-8, Compound 1-10, Compound 1-15, Compound 1-16, Compound1-17, Compound 1-18, Compound 1-19, Compound 1-20, Compound 1-21,Compound 1-23, Compound 1-24, Compound 1-25, Compound 1-42, Compound1-43, Compound 144, Compound 145, Compound 1-46, Compound 1-47, Compound1-48, Compound 1-49, Compound 1-50, Compound 1-51, Compound 1-52,Compound 1-53, Compound 1-54, Compound 1-55, Compound 1-56, Compound1-57, Compound 1-58, Compound 1-61, Compound 1-62, Compound 2-2,Compound 2-3, Compound 2-4, Compound 2-5, Compound 2-6, Compound 2-7,Compound 2-8, Compound 2-9, Compound 2-11, Compound 3-4, and Compound3-5, is shown in Tables 1-3. NMR data for Compound 1-9 is shown below.

Notes:

For Compound 1-9, i) only Steps 1 and 3 were performed, ii) ¹H NMR(CD3OD, 400 MHz), d 7.13 (d, 1H), 7.09 (m, 3H), 6.81 (m, 3H), 5.49 (s,2H), 4.35 (m, 1H), 4.05 (dd, 1H), 4.01 (dd, 1H), 3.36 (m, 1H), 2.76 (appq, 1H), 2.23 (m, 1H), 2.19-1.85 (m's, 3H), 1.12 (s, 9H), 1.07 (s, 6H).

For Compound 1-15, only Steps 1 and 3 were performed.

For Compound 1-17, after Step 2, the 3-tert-butylsulfanyl in theprecursor was oxidized with m-chloroperoxybenzoic acid to give the2-methylpropane-2-sulfonyl in the final product.

For Compound 1-23, only Steps 1 and 3 were performed.

For Compound 1-25, after Step 3, the 3-tert-butylsulfanyl in theprecursor was oxidized with m-chloroperoxybenzoic acid to give the2-methylpropane-2-sulfinyl in the final product.

For Compound 1-62, only Steps 1 and 3 were performed.

For Compound 2-2, only Steps 1 and 3 were performed.

For Compound 2-11, Steps 2 and 3 were performed in the reverse order.

For Compound 34, only Steps 1 and 2 were performed.

For Compound 3-5, only Steps 1 and 2 were performed.

Example 8 Preparation of Compound 1-26, Compound 1-27, Compound 1-28,Compound 1-29, Compound 1-30, Compound 1-31, Compound 1-32, Compound1-33, Compound 1-34, Compound 1-35, Compound 1-36, Compound 1-37,Compound 1-38, Compound 1-39, Compound 1-40, and Compound 1-41.

Compound 1-26, Compound 1-27, Compound 1-28, Compound 1-29, Compound1-30, Compound 1-31, Compound 1-32, Compound 1-33, Compound 1-34,Compound 1-35, Compound 1-36, Compound 1-37, Compound 1-38, Compound1-39, Compound 1-40, and Compound 1-41, were prepared as shown in SchemeH. A detailed illustrative example of the reaction conditions shown inScheme H is described for the synthesis of3-{5-(benzothiazol-2-ylmethoxy)-3-cyclobutylmethyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid.

Step 1:3-[5-(Benzothiazol-2-ylmethoxy)-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl]-2,2-dimethyl-propionicacid ethyl ester

Aluminum chloride (0.18 g, 1.37 mmol) was suspended in CH₂Cl₂ (1 mL),and water (19 uL, 1.0 mmol) was added slowly at room temperature. Themixture was stirred for 5 minutes, and then cooled to 0° C.3-{5-(Benzothiazol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester (0.12 g, 0.17 mmol) was added in CH₂Cl₂ (1 mL), and thereaction was stirred at room temperature for 2 hours. Once no startingmaterial was observed by tlc, water was added and the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed withwater, dried over MgSO₄, filtered, and concentrated. The residue waspurified to give the desired product (H-1).

Step 2:3-{5-(Benzothiazol-2-ylmethoxy)-3-cyclobutanecarbonyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

To H-1 (0.10 g, 0.17 mmol) in dichloroethane (5 mL) was addedcyclobutanecarbonyl chloride (57 uL, 0.50 mmol) and aluminum chloride(0.09 g, 0.66 mmol). The reaction was heated under N₂ for 1.5 hours, andthen cooled to room temperature and quenched with saturated aq.potassium sodium tartrate. The mixture was extracted with EtOAc, and thecombined organic layers were dried over MgSO₄, filtered, concentrated,and purified on silica gel to give the desired product (H-2).

Step 3:3-{5-(Benzothiazol-2-ylmethoxy)-3-cyclobutylmethyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid ethyl ester

H-2 (0.05 g, 0.08 mmol) was suspended in CH₂Cl₂, and sodium borohydride(0.03 g, 0.8 mmol) was added dropwise in TFA (1 mL) and CH₂Cl₂ (1 mL).The mixture was stirred at room temperature for 4 hours, and thenquenched with water and basified with solid NaOR pellets. The mixturewas extracted with CH₂Cl₂, and the combined organics were dried overMgSO₄, filtered, and concentrated. The residue was purified on silicagel to give the desired product (H-3).

Step 4:3-{5-(Benzothiazol-2-ylmethoxy)-3-cyclobutylmethyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionicacid

H-3 (0.03 g, 0.04 mmol) was dissolved in MeOH (0.5 mL) and THF (0.5 mL).Aq. lithium hydroxide (1N, 0.5 mL) was added, and the reaction washeated at 60° C. for 4 hours until no starting material was seen byLCMS. The reaction was diluted with water, acidified to pH 5 with citricacid, and extracted with EtOAc. The combined organic layers were washedwith water, dried over MgSO₄, filtered, and concentrated to give thedesired product (H-4).

Mass spectrometry data for Compound 1-26, Compound 1-27, Compound 1-29,Compound 1-30, Compound 1-31, Compound 1-32, Compound 1-33, Compound1-34, Compound 1-35, Compound 1-36, Compound 1-37, Compound 1-38,Compound 1-39, Compound 140, and Compound 1-41, is shown in Tables 1-3.NMR data for Compound 1-28 is shown below.

Notes:

For Compound 1-27, only Steps 1 and 4 were performed.

For Compound 1-28, i) only Steps 1 and 4 were performed, ii) ¹H NMR(CDCl₃, 300 MHz, rotamers) d 7.18 (m, 2H), 7.07 (s, 1H), 7.07-6.94 (m,2H), 6.79-6.69 (m, 3H), 6.34 (m, 1H) 5.29 (m, 2H), 4.46-3.41 (m's, 7H),2.93 (m, 2E), 2.29-1.92 (7H), 1.26 (m, 6H).

For Compound 1-29, only Steps 1, 2, and 4 were performed.

For Compound 1-30, only Steps 1, 2, and 4 were performed.

For Compound 1-33, only Steps 1, 2, and 4 were performed.

For Compound 1-34, only Steps 1, 2, and 4 were performed.

For Compound 1-35, only Steps 1, 2, and 4 were performed.

For Compound 1-36, only Steps 1, 2, and 4 were performed.

For Compound 1-37, only Steps 1, 2, and 4 were performed.

For Compound 1-38, only Steps 1, 2, and 4 were performed.

Example 93-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamideStep 1:3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-2,2-dimethyl-propionylchloride

To3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-2,2-dimethyl-propionicacid (prepared according to the procedures described in U.S. Pat. No.5,081,138 issued Jan. 14, 1992; 0.25 g, 0.53 mmol) suspended in CH₂Cl₂(5 mL) was added oxalyl chloride (48 uL, 0.56 mmol) and catalytic DMF.The reaction was stirred at room temperature for 3 hours, and thenconcentrated to give I-1, which was used without further purification.

Step 2:3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-N-(2-hydroxy-ethyl)-2,2-dimethyl-propionamide

To I-1 (0.18 mmol) in CH₂Cl₂ was added triethylamine (0.1 mL, 0.70 mmol)and 2-aminoethanol (10 uL, 0.19 mmol). The reaction was stirred for 2days at room temperature, and then concentrated and purified on silicagel (EtOAc:hexanes gradient) to give the desired product (1-2).

Step 3:5-{4-[3-tert-Butylsulfanyl-2-(2,2-dimethyl-propyl)-5-(pyridin-2-ylmethoxy)-indol-1-ylmethyl]-phenyl}-[1,3,4]oxadiazol-2-ylamine

To4-[3-tert-Butylsulfanyl-2-(2,2-dimethyl-propyl)-5-(pyridin-2-ylmethoxy)-indol-1-ylmethyl]-benzoicacid hydrazide (0.05 g, 0.10 mmol) in DMF (1 mL) was addedC-(Di-imidazol-1-yl)-methyleneamine (0.08 g, 0.50 mmol), and thereaction was heated at 85° C. for 3 hours. The mixture was cooled toroom temperature and partitioned between water and EtOAc. The aqueouslayer was extracted with EtOAc, and the combined organic layers weredried over MgSO₄, filtered, and concentrated. The residue was purifiedon silica gel (EtOAc:hexane gradient) to give the desired product.

Example 10 FLAP Binding Assays

A non-limiting example of such a FLAP binding assay is as follows:Packed human polymorphonuclear cell pellets (1.8×109 cells) (BiologicalSpeciality Corporation) were resuspended, lysed and 100,000 g membranesprepared as described (Charleson et al. Mol. Pharmacol, 41, 873-879,1992). 100,000×g pelleted membranes were resuspended in Tris-Tween assaybuffer (100 mM Tris HCl pH 74, 140 mM NaCl, 2 mM EDTA, 0.5 mM DTT, 5%glycerol, 0.05% Tween 20) to yield a protein concentration of 50-100ug/mL. 10 uL membrane suspension was added to 96 well Millipore plate,78 μL Tris-Tween buffer, 10 μL ³H MK886 or ³H3-[5-(pyrid-2-ylmethoxy)-3-tert-butylthio-1-benzyl-indol-2-yl]-2,2-dimethylpropionicacid (or ¹²⁵I MK591 derivative Eggler et al, J. Labelled Compounds andRadiopharmaceuticals, 1994, vXXXrV, 1147)) to ˜30,000 cpm, 2 μLinhibitor and incubated for 30 minutes at room temperature. 100 μLice-cold washed buffer was added to the incubation mixture. Plates werethen filtered and washed 3× with 200 μL ice cold Tris-Tween buffer,scintillation bottoms sealed, 100 μL scintillant added, shaken for 15minutes then counted in a TopCount. Specific binding was determined asdefined as total radioactive binding minus non-specific binding in thepresence of 10 μM MK886. IC50s were determined using Graphpad prismanalysis of drug titration curves.

Example 11 Human Blood LTB₄ Inhibition Assay

A non-limiting example of such a human blood LTB₄ inhibition assay is asfollows: Blood was drawn from consenting human volunteers intoheparinized tubes and 125 μL aliquots added to wells containing 2.5 μL50% DMSO (vehicle) or 2.5 μL drug in 50% DMSO. Samples were incubatedfor 15 minutes at 37° C. 2 μL calcium ionophore A23817 (from a 50 mMDMSO stock diluted just prior to the assay in Hanks balanced saltsolution (Invitrogen)) to 1.25 mM) was added, solutions mixed andincubated for 30 minutes at 37° C. Samples were centrifuged at 1,000 rpm(˜200×g) for 10 minutes at 4° C., plasma removed and a 1:100 dilutionassayed for LTB₄ concentration using ELISA (Assay Designs). Drugconcentrations to achieve 50% inhibition (IC50 's) of vehicle LTB₄ weredetermined by nonlinear regression (Graphpad Prism) of % inhibitionversus log drug concentration.

Example 12 Rat Peritoneal Inflammation and Edema Assay

A non-limiting example of such a rat peritoneal inflammation and edemaassay is as follows:

The in vivo efficacy of leukotriene biosynthesis inhibitors was assessedusing a rat model of peritoneal inflammation. Male Sprague-Dawley rats(weighing 200-300 grams) received a single intraperitoneal (i.p.)injection of 3 mL saline containing zymosan (5 mg/mL) followedimmediately by an intravenous (i.v.) injection of Evans blue dye (2 mLof 1.5% solution). Compounds were administered orally (3 mL/kg in 0.5%methylcellulose vehicle) 2 to 4 hours prior to zymosan injection. One totwo hours after zymosan injection, rats were euthanized, and theperitoneal cavity was flushed with 10 mL phosphate buffered salinesolution (PBS). The resulting fluid was centrifuged at 1,200 rpm for 10minutes. Vascular edema was assesses by quantifying the amount of Evansblue dye in the supernatant using a spectrophotometer (Absorbance 610nm). LTB₄ and cysteinyl leukotriene concentrations in the supernatantwere determined by ELISA. Drug concentrations to achieve 50% inhibitionof plasma leakage (Evans blue dye) and inhibition of peritoneal LTB₄ andcysteinyl leukotrienes could be calculated by nonlinear regression(Graphpad Prism) of % inhibition versus log drug concentration.

Example 13 Human Leukocyte Inhibition Assay

A non-limiting example of a human leukocyte inhibition assay is asfollows: Blood was drawn from consenting human volunteers intoheparanized tubes and 3% dextran, 0.9% saline equal volume added. Aftersedimentation of red blood cells a hypotonic lysis of remaining redblood cells was performed and leukocytes sedimented at 1000 rpm. Thepellet was resuspended at 1.25×10⁵ cells/mL and aliquoted into wellscontaining 2.5 μL 20% DMSO (vehicle) or 2.5 μL drug in 20% DMSO. Sampleswere incubated for 5 minutes at 37° C. and 2 μL calcium ionophore A23817(from a 50 mM DMSO stock diluted just prior to the assay in Hanksbalanced salt solution (Invitrogen)) to 1.25 mM) was added, solutionsmixed and incubated for 30 minutes at 37° C. Samples were centrifuged at1,000 rpm (˜200×g) for 10 minutes at 4° C., plasma removed and a 1:4dilution assayed for LTB₄ concentration using ELISA (Assay Designs).Drug concentrations to achieve 50% inhibition (IC₅₀'s) of vehicle LTB₄were determined by nonlinear regression (Graphpad Prism) of % inhibitionversus log drug concentration. The compounds presented in Tables 1-4 hadassays of 1 nM to 5 μM with this assay.

Example 14 Rat Bronchioalveolar Lavage Procedure

A non-limiting example of a rat bronchioalveolar lavage assay is asfollows: A rat ionophore lung lavage model was utilized to determineefficacy of leukotriene biosynthesis inhibitors in the target tissue forrespiratory therapy. Male Sprague-Dawley rats (weighing 200-300 grams)were administered compound orally (3 ml/kg in 0.5% methylcellulosevehicle) 2 to 24 hours prior to lung lavage. At the appropriate timeafter compound administration rats were placed into an enclosedPlexiglas chamber and exposed to CO₂ for a period of 1-2 minutes oruntil breathing ceased. They were then removed and blood was taken via acardiac puncture. Cervical dislocation was performed to ensure ratswould not recover from the CO₂. Subjects were next placed in a supineposition, the trachea was exposed by blunt dissection and a 7 ml bolusof ice cold phosphate buffered saline solution (PBS with 7% DMSO)containing 20 μg/ml A23187 was instilled using a 10 ml syringe equippedwith a 20 gauge blunt needle tip. After a 3-minute period the fluid waswithdrawn, mixed with equal parts ice cold methanol and centrifuged at10,000×g for 10 minutes at 4° C. LTB₄ and cysteinyl leukotrieneconcentrations in the supernatant were determined by EIA. Drugconcentrations to achieve 50% inhibition of lung, LTB₄ and cysteinylleukotrienes could be calculated by nonlinear regression (GraphpadPrism) of % inhibition versus log drug concentration.

Example 15 Pharmaceutical Compositions Example 15a ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of any of Formula (E), Formula (E-I), or Formula (E-II), isdissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. Themixture is incorporated into a dosage unit form suitable foradministration by injection.

Example 15b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of any of Formula (E), Formula (E-I), or Formula (E-II), ismixed with 750 mg of starch. The mixture is incorporated into an oraldosage unit for, such as a hard gelatin capsule, which is suitable fororal administration.

Example 15c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of any of Formula (E), Formula(E-I), or Formula (E-II), with 420 mg of powdered sugar mixed, with 1.6mL of light corn syrup, 2.4 mL distilled water, and 0.42 mL mintextract. The mixture is gently blended and poured into a mold to form alozenge suitable for buccal administration.

Example 15d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of any of Formula (E), Formula (E-I), or Formula (E-II),is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodiumchloride solution. The mixture is incorporated into an inhalationdelivery unit, such as a nebulizer, which is suitable for inhalationadministration.

Example 15e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of any of Formula (E), Formula (E-I), or Formula (E-II), ismixed with 2.5 g of methylcelluose (1500 mPa), 100 mg of methylparapen,5 g of glycerin and 100 mL of purified water. The resulting gel mixtureis then incorporated into rectal delivery units, such as syringes, whichare suitable for rectal administration.

Example 15f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of any of Formula (E), Formula (E-I), or Formula (E-II), ismixed with 1.75 g of hydroxypropyl celluose, 10 mL of propylene glycol,10 mL of isopropyl myristate and 100 mL of purified alcohol USP. Theresulting gel mixture is then incorporated into containers, such astubes, which are suitable for topical administration.

Example 15g Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of any of Formula (E), Formula (E-I), or Formula (E-II), ismixed with 0.9 g of NaCl in 100 mL of purified water and filtered usinga 0.2 micron filter. The resulting isotonic solution is thenincorporated into ophthalmic delivery units, such as eye dropcontainers, which are suitable for ophthalmic administration.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims. All publications,patents, and patent applications cited herein are hereby incorporated byreference for all purposes.

1. A compound having the structure of Formula (E):

wherein, Z is OC(R₁)₂[C(R₂)₂]_(n), [C(R₂)₂]_(n), or [C(R₂)₂]_(n)C(R₁)₂O wherein each R₁ is independently H, CF₃, or an optionally substituted lower alkyl; or two R₁ on the same carbon may join to form an oxo (═O); and each R₂ is independently H, OH, OMe, CF₃, or an optionally substituted lower alkyl; or two R₂ on the same carbon may join to form an oxo (═O); each n is independently 0, 1, 2, or 3; Y is -L₁-(substituted or unsubstituted heteroalicyclic group), provided that when the heteroatom is directly bound to Z, the heteroalicyclic group is substituted; where L₁ is a bond, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, a substituted or unsubstituted heterocycle, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, or a substituted or unsubstituted heteroalkynyl; where each substituent is (L_(s)R_(s))_(j), wherein each L_(s) is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)O—, —NHC(O)NH—, —C(O)O—, —OC(O)—, C₁-C₆ alkyl, C₂-C₆ alkenyl, —C₁-C₆ fluoroalkyl, heteroaryl, aryl, or heteroalicyclic group; and each R_(s) is independently selected from H, halogen, —N(R₄)₂, —CN, —NO₂, N₃, —S(═O)₂NH₂, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, —C₁-C₆ fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl or substituted or unsubstituted heteroalkyl; or R_(s) is (R_(t)L_(s)R_(s)) wherein each R_(t) is independently selected from a bond, —N(R₄), substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, —C₁-C₆ fluoroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicycle or substituted or unsubstituted heteroalkyl; where j is 0, 1, 2, 3, or 4; each R₄ is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R₄ groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or unsubstituted alkenyl), L₂-(substituted or unsubstituted cycloalkenyl), L₂-(substituted or unsubstituted heteroalicyclic group), L₂-(substituted or unsubstituted heteroaryl), or L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S, —S(═O), —S(═O)₂, C(O), —CH(OH), -(substituted or unsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted C₂-C₆ alkenyl); R₇ is L₃-X-L₄-G₁, wherein, L₃ is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclic group; X is a bond, O, —C(═O), —CR₉(OR₉), S, —S(═O), —S(═O)₂, —NR₉, —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₄ is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; G₁ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, NR₉C(═CHR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CHR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted or unsubstituted aryl), wherein L₅ is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or G₁ is W-G₅, where W is a substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G₅ is H, tetrazolyl, —NHS(═O)₂R₉, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CHR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CHR₁₀)N(R₉), —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈; each R₈ is independently selected from substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; each R₉ is independently selected from H, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower cycloalkyl, phenyl or benzyl; or two R₉ groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring and each R₁₀ is independently selected from H, —S(═O)₂R₈, —S(═O)₂NH₂, —C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl; R₅ is H, halogen, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted O—C₁-C₆ alkyl; R₁₁ is L₇-L₁₀-G₆; wherein L₇ is a bond, —O, —S, —S(═O), —S(═O)₂, —NH, —C(O), —C(O)NH, —NHC(O), (substituted or unsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); L₁₀ is a bond, (substituted or unsubstituted alkyl), (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted heteroaryl), (substituted or unsubstituted aryl), or (substituted or unsubstituted heteroalicyclic group), and G₆ is H, CN, SCN, N₃, NO₂, halogen, OR₉, —C(═O)CF₃, —C(═O)R₉, —SR₈, —S(═O)R₈, —S(═O)₂R₈, N(R₉)₂, tetrazolyl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CHR₁₀)N(R₂)₂, -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted or unsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or G₆ is W-G₇, wherein W is (substituted or unsubstituted cycloalkyl), (substituted or unsubstituted cycloalkenyl), (substituted or unsubstituted aryl), (substituted or unsubstituted heteroalicyclic group) or a (substituted or unsubstituted heteroaryl) and G₇ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, NR₉C(═CHR₁₀)N(R₉)₂—C(O)NR₉C(═NR₁₀)N(R₉)₂, C(O)NR₉C(═CHR₁₀)N(R₂)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈, -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted or unsubstituted heteroalkyl), -L₅-(substituted or unsubstituted heteroaryl), -L₅-(substituted or unsubstituted heteroalicyclic group), or -L₅-(substituted or unsubstituted aryl), wherein L₅ is —NH, —NHC(O)O, —NHC(O)NH—, —OC(O)O—, —OC(O)NH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); R₁₂ is H, (substituted or unsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted C₃-C₆ cycloalkyl); or an active metabolite, or solvate, or pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
 2. The compound of claim 1, wherein L₁ is a bond or substituted or unsubstituted alkyl.
 3. The compound of claim 2, wherein the heteroalicyclic group of Y is selected from the group consisting of a quinolizine, a dioxine, a piperidine, a morpholine, a thiazine, a tetrahydropyridine, a piperazine, a oxazinanone, a dihydropyrrole, a dihydroimidazole, a tetrahydrofuran, a dihydrooxazole, an oxirane, a pyrrolidine, a pyrazolidine, a dihydrothiophenone, an imidazolidinone, a pyrrolidinone, a dihydrofuranone, a dioxolanone, a thiazolidine, a piperidinone, a tetrahydronaphyridine, a tetrahydroquinoline, a tetrahydrothiophene, an indoline, a tetrahydroquinoline, and a thiazepane.
 4. The compound of claim 3, wherein the heteroalicyclic group of Y is selected from the group consisting of a piperidine, a morpholine, a tetrahydrofuran, a pyrrolidine, a pyrrolidinone, a thiazolidine, a piperidinone, a tetrahydroquinoline, an indoline, wherein the heteroalicyclic group is substituted or unsubstituted.
 5. The compound of claim 1, wherein R₆ is L₂-(substituted or unsubstituted alkyl), or L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S, —S(O)₂, —C(O), —CH(OH), or substituted or unsubstituted alkyl.
 6. The compound of claim 1, wherein R₇ is L₃-X-L₄-G₁; wherein, L₃ is a substituted or unsubstituted alkyl; X is a bond, O, —C(═O), —CR₉(OR₉), S, —S(═O), —S(═O)₂, —NR₉, —NR₉C(O), —C(O)NR₉, —S(═O)₂NR₉—, —NR₉S(═O)₂, —OC(O)NR₉—, —NR₉C(O)O—, —CH═NO—, —ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; and L₄ is a bond or a substituted or unsubstituted alkyl.
 7. The compound of claim 6, wherein G₁ is tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, —OR₉, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₉)₂, —N(R₉)C(O)R₉, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(—NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, or G₁ is W-G₅, where W is a substituted or unsubstituted heteroalicyclic group or substituted or unsubstituted heteroaryl and G₅ is tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉)₂, OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₉, CN, N(R₈)₂, —N(R₉)C(O)R₈, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R)₂, —CO₂R₉, —C(O)R₉, —CON(R₉)₂, —SR₈, —S(═O)R₈, or —S(═O)₂R₈.
 8. The compound of claim 7, wherein X is a bond, —O—, —CR₉(OR₉), S, —S(O), —S(O)₂, —NR₈, —O—N═CH, —CH═N—O, —NHC(═O) or —C(═O)NH.
 9. The compound of claim 1, wherein R₁₂ is H and R₁₂ is L₇-L₁₀-G₆, wherein L₇ is a bond, (substituted or unsubstituted C₁-C₆ alkyl), and L₁₀ is a (substituted or unsubstituted aryl), (substituted or unsubstituted heteroaryl), or (substituted or unsubstituted heteroalicyclic group).
 10. The compound of claim 9, wherein L₁₀ is a (substituted or unsubstituted aryl).
 11. The compound of claim 9, wherein G₆ is W-G₇, wherein W is (substituted or unsubstituted heteroalicyclic group) or (substituted or unsubstituted heteroaryl) and G₇ is H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, N(R₉)₂, —C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —C(O)NR₉C(═NR₁₀)N(R₉)₂, —C(O)NR₉C(═CR₁₀)N(R₉)₂, —CON(R₉)₂, -L₅-(substituted or unsubstituted alkyl), -L₅-(substituted or unsubstituted heteroaryl), -L₅-(substituted or unsubstituted heteroalicyclic group), or -L₅-(substituted or unsubstituted aryl), L₅ is —OC(O)O—, —NHC(O)NH—, —NHC(O)O, —O(O)CNH—, —NHC(O), —C(O)NH, —C(O)O, or —OC(O).
 12. The compound of claim 1, wherein the compound of Formula (E) is an inhibitor of 5-lipoxygenase-activating protein and/or LTC4.
 13. The compound of claim 12, wherein the inhibitor is selective for FLAP.
 14. The compound of claim 13, wherein the inhibitor has an IC₅₀ of below 50 microM in FLAP binding.
 15. A compound selected from among: (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 1-1); 3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-2); (R)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 1-3); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-5-oxo-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-4); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-5-oxo-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-5); 3-[5-((R)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-6); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-7); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-8); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-9); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(2,2,2-trifluoro-acetyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-10); 2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (Compound 1-11); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-12); (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (Compound 1-13); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2-morpholin-4-yl-2-oxo-ethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-14); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[(S)-1-(2,3-dihydro-1H-indol-2-yl)methoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-15); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-16); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(2-methyl-propane-2-sulfonyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-17); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-cyclopropanecarbonyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-18); 3-[5-((S)-1-benzoyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-19); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-isobutyryl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-20); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-propionyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-21); 2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (Compound 1-22); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(2,3-dihydro-1H-indol-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 12-23); 3-[5-(1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-24); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(2-methyl-propane-2-sulfinyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-25); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-benzyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-26); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-27); 3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-28); 3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyryl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-29); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyryl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-30); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-ethyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-31); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-propyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 13-32); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-isobutyryl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-33); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclopropanecarbonyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-34); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-benzoyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-35); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclobutanecarbonyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-36); 3-[3-acetyl-5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-37); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-propionyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-38); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-isobutyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-39); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-(3,3-dimethyl-butyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-40); 3-[5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1-(4-chloro-benzyl)-3-cyclobutylmethyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-41); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-ylmethoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-42); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(1-phenylacetyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-43); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenyl-propionyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-44); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenoxy-benzoyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-45); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(4-phenoxy-benzoyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-46); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-47); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-48); 3-[5-[1-(biphenyl-4-carbonyl)-pyrrolidin-2-ylmethoxy]-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (Compound 1-49); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-(1-phenylacetyl-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (Compound 1-50); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(3-phenyl-propionyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (Compound 1-51); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-((S)-2-phenyl-cyclopropanecarbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (Compound 1-52); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-3-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (Compound 1-53); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-(pyridine-4-carbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (Compound 1-54); 3-{3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-[1-((R)-2-phenyl-cyclopropanecarbonyl)-pyrrolidin-2-ylmethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-55); 3-[3-tert-butylsulfanyl-5-[(S)-1-(4-chloro-benzoyl)-pyrrolidin-2-ylmethoxy]-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-56); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-ylmethoxy}-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-57); 3-[5-{1-[2-(4-benzyloxy-phenyl)-acetyl]-pyrrolidin-2-ylmethoxy}-3-tert-butylsulfanyl-1-(4-chloro-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (Compound 1-58); 2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-chloro-benzyl)-1H-indol-5-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound 1-59); 2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-ethoxycarbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (Compound 1-60); 2-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-2-(2-ethoxycarbonyl-2-methyl-propyl)-1H-indol-5-yloxymethyl]-2,3-dihydro-indole-1-carboxylic acid 2-bromo-ethyl ester (Compound 1-61); 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-pyrrolidin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 1-62); 3-{1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 1-63); (S)-2-[3-tert-butylsulfanyl-2-(2-carboxy-2-methyl-propyl)-1-(4-thiazol-2-yl-benzyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 2-1); 3-[3-tert-butylsulfanyl-5-((S)-1-pyrrolidin-2-ylmethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 2-2); 3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 2-3); 3-[5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-1-(4-thiazol-2-yl-benzyl)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (Compound 2-4); 3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-5); 3-{5-((S)-1-acetyl-pyrrolidin-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-6); 3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-7); 3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(2-methoxy-thiazol-4-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-8); 3-{5-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-9); 3-{3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethoxy]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-10); 3-{3-tert-butylsulfanyl-5-[(S)-1-(2-methoxy-acetyl)-2,3-dihydro-1H-indol-2-ylmethoxy]-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (Compound 2-11); 2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxy]-1-morpholin-4-yl-ethanone (Compound 3-1); (R)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-2); (R)-2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-3); 1-{(R)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(2-hydroxy-2-methyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidin-1-yl}-ethanone (Compound 3-4); 1-{(R)-2-[3-tert-butylsulfanyl-2-(2-hydroxy-2-methyl-propyl)-1-pyridin-2-ylmethyl-1H-indol-5-yloxymethyl]-pyrrolidin-1-yl}-ethanone (Compound 3-5); and (S)-2-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-2-(3-hydroxy-2,2-dimethyl-propyl)-1H-indol-5-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (Compound 3-6).
 16. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
 17. A method for treating inflammation in a mammal comprising administering a therapeutically effective amount of a compound of claim 1 to the mammal in need.
 18. A method for treating respiratory disease in a mammal comprising administering a therapeutically effective amount of a compound of claim 1 to the mammal in need.
 19. The method of claim 18, wherein Z is [C(R₂)₂]_(n)C(R₁)₂O.
 20. A method for treating cardiovascular disease in a mammal comprising administering a therapeutically effective amount of a compound of claim 1 to the mammal in need. 